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Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review
ARTICLES
Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review
John R Geddes, Stuart M Carney, Christina Davies, Toshiaki A Furukawa, David J Kupfer, Ellen Frank, Guy M Goodwin
Summary Background Antidepressant drugs can promote remission from acute depressive episodes. Our aim was to establish how long such treatments should be continued to prevent relapse. Method We did a systematic overview of evidence from randomised trials of continuing treatment with antidepressants in patients with depressive disorders who have responded to acute treatment. Medline, Embase, Cinahl, PsycLIT, Psyndex, and Lilacs were searched. Findings Data were pooled from 31 randomised trials (4410 participants). Continuing treatment with antidepressants reduced the odds of relapse by 70% (95% CI 62–78; 2p<0·00001) compared with treatment discontinuation. The average rate of relapse on placebo was 41% compared with 18% on active treatment. The treatment effect seemed to persist for up to 36 months, although most trials were of 12 months’ duration, and so the evidence on longer-term treatment requires confirmation. Significantly more participants allocated antidepressants withdrew from the trials than did those allocated to placebo (18% vs 15%, respectively; odds ratio 1·30, 95% CI 1·07–1·59): the treatment effect could be even greater in adherent patients. The two-thirds reduction in risk of depressive relapse seemed to be largely independent of the underlying risk of relapse, the duration of treatment before randomisation, or the duration of the randomly allocated therapy. Interpretation Antidepressants reduce the risk of relapse in depressive disorder, and continued treatment with antidepressants would benefit many patients with recurrent depressive disorder. The treatment benefit for an individual patient will depend on their absolute risk of relapse with greater absolute benefits in those at higher risk. Further trials are needed to establish the optimum length of therapy and should include patients who were not well represented in these trials, including those at low risk of relapse. Lancet 2003; 361: 653–51
Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK (Prof J R Geddes MD, S M Carney MRCPsych, Prof G M Goodwin FRCPsych); Clinical Trial Service Unit, University of Oxford, Radcliffe Infirmary, Oxford (C Davies MBChB); Department of Psychiatry, Nagoya City University Medical School, Mizuho-cho, Mizuho-ku, Nagoya, Japan (Prof T A Furukawa MD); and Department of Psychiatry, UPMC Health System, Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA (Prof D J Kupfer MD, Prof E Frank PhD) Correspondence to: Prof John Geddes, University of Oxford, Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX, UK. (e-mail: [email protected])
THE LANCET • Vol 361 • February 22, 2003 • www.thelancet.com
Introduction Neuropsychiatric illnesses in general and unipolar depressive disorder in particular are among the most important causes of death and disability worldwide, in both developing and developed countries.1,2 Short-term and medium-term therapy with antidepressant drugs is already standard treatment for acute episodes of depression.3 However, because of the long-term nature of depressive disorder, with many patients at substantial risk of later recurrence, there is a considerable need to establish how long, in general, such patients should stay on antidepressants. Clinical guidelines recommend that treatment should be continued for 4–6 months after the acute episode (panel). However, there is considerable variation in practice, suggesting that many patients do not receive optimum treatment.8 We aimed systematically to review evidence from randomised trials to determine whether continuing treatment with antidepressants reduces the risk of relapse (ie, a return of symptoms during a period of remission or partial remission) or recurrence (ie, a new episode during a period of recovery) of depressive symptoms. In addition, we assessed whether the magnitude of this benefit varies according to the length of previous treatment, length of continuing treatment, and the underlying level of risk of relapse.
Methods Data acquisition The aim of this systematic review was to identify all randomised trials, published or unpublished, available for review by August, 2000, in which continued antidepressant drug therapy was compared with placebo in patients who had responded to acute treatment with antidepressants.
Search strategy Electronic databases The Cochrane collaboration depression, anxiety, and neurosis controlled trials register (CCDANCTR), which incorporates results of group searches of Medline (1966, to April, 2000); Embase (1980, to April, 2000); Cinahl (1982, to April, 2000); PsycLIT (1974, to April, 2000); Psyndex (1977, to December, 1999); and Lilacs (1982, to December, 1999) were searched with the following terms: #45 (diagnosis field)=depression* or depressive-disorder or dysthymi* and (maintenance* or maintain* or continu* or preventive) and #30 (intervention field)=pharmacotherapy.* The Cochrane controlled trials register was searched with the same terms as for CCDANCTR, but excluded references tagged with sr-depress* because they were already obtained from CCDANCTR. Reference checking the reference lists of all selected studies were inspected for additional published reports and citations of unpublished research. Other relevant papers and major textbooks that cover mood disorder were checked. Personal communications authors of identified papers, experts in the field, and drug companies that manufacture antidepressants were contacted
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ARTICLES
Guidelines for duration of antidepressant treatment after acute treatment response Recommended duration of continuation* after medical management of the acute episode (months)
Number of episodes that would indicate longer "maintenance" treatment is appropriate
UK defeat depression consensus statement4
4–6
⭓2
US Agency for Health Care Policy and Research5
4–9
⭓3
British Association for Psychopharmacology6
6
⭓3 in past 5 years (or ⭓6 in total)
American Psychiatric Association7
4–5
Not specified
Quality assessment Two reviewers (TF and GG) assessed independently the methodological quality of eligible trials. A qualitative assessment was made by investigation of those aspects of trial design generally considered to be most crucial for internal validity—namely, methods of randomisation and prior concealment of treatment allocation from investigators and patients; masking the identity of the randomly allocated treatment from the investigator and participant (for example, by use of a placebo control); masking the allocated treatment from the outcome assessor; reporting withdrawals and dropouts; and the method of analysis (intention-to-treat analyses were judged clinically most useful and more statistically robust than other types of analysis). If adequate details of these characteristics of trials were not provided in the published reports of the trials, we contacted the authors to obtain further information.
Trials in which patients were randomly allocated treatment after acute treatment response were included, along with those in which patients were randomised after a variable period of continuing therapy.
Data extraction Two reviewers (SC and CD) extracted data about participants’ characteristics, intervention details (including whether or not the study was of a discontinuation design), and outcome measures from the included studies. A further reviewer (JG) checked the data. Data were entered into review manager software (version 4.1). Relapse or recurrence was counted according to the original authors’ definitions.
Selection of trials The search results were checked independently by two reviewers (SC and JG) and all potentially suitable studies were requested. SC and CD checked independently all identified studies. Any disagreements as to whether a study should be included were resolved by discussion with a third member (JG). Trials were eligible for the review if: (1) they included patients with depressive disorders who had either responded to treatment for an acute episode, or who had remained free from depressive illness for a period on antidepressants following initial response to treatment; and (2) patients were then randomly allocated to continue or discontinue treatment and were followed up for a minimum of 1 month.
Data analysis The published reports did not provide enough information to allow a meta-analysis of time-to-relapse data. We therefore used tabulated data on total relapse rates at a specific point after randomisation. Both relative and absolute treatment effects were calculated. The relative effects of treatment (eg, a halving of risk) might well be more generalisable than the absolute effects,9 but the absolute effects are more directly relevant to helping clinicians make informed treatment decisions in specific clinical situations. In the simplest summaries of overall trial results, all treatment and control groups were added together and the proportions of patients relapsing in each group were
*At same dose.
Number of trials NARI
2
MAOI
4
Tricyclic
15
SSRI
10
Other
1
Total
99% or
32
Events/patients Allocated Placebo antidepressant adjusted 169/912 (19%) 13/61 (21%) 113/449 (25%) 156/1034 (15%) 14/71 (20%)
313/889 (35%) 57/66 (86%) 248/432 (57%) 385/1046 (37%) 28/72 (39%)
465/ 2527 (18%)
1031/ 2505 (41%)
Antidepressant events Logrank (Variance O–E of O–E) –57·5
(60·7)
–15·7
(6·0)
–70·7
(50·5)
–94·9
(80·7)
–6·9
(7·5)
–245·7
(205·4)
Odds ratio (95% CI) Antidepressant : Placebo
Reduction (SE)
70% (4) 2p<0·00001
95% confidence intervals 0
Heterogeneity between five categories: 24=18·6; p=0·001
0·5 1·0 1·5 2·0 Antidepressant better Antidepressant worse Treatment effect 2p<0·00001
Figure 1: Risk of relapse: odds ratios by drug type NARI=noradrenaline (norepinephrine) reuptake inhibitor. MAOI=monoamine oxidase inhibitor. SSRI=selective serotonin reuptake inhibitor.
654
THE LANCET • Vol 361 • February 22, 2003 • www.thelancet.com
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ARTICLES
Months of treatment Prerandomised* Randomised
Events/patients Adjusted Allocated placebo antidepressant
Antidepressant events Logrank (Variance O–E of O–E)
Odds ratio (95%) Antidepressant : Placebo
Reduction (SE)
(a) 1–2 months before randomisation ± 6 months study treatment Davidson17 Harrison24 Klerman30 Klerman30 Lendresse34 Mindham35 Mindham35 Montgomery37 Robert43
1 1·5 2 2 2 2 2 1·5 2
6 6 6 6 6 6 6 6 6
1/9 1/5 3/25 3/25 14/71 8/34 3/16 11/105 21/152
8/9 7/7 7/25 7/25 28/72 18/27 3/15 2 (13/42) 2 (18/74)
65/442
140/412
(15%)
(34%)
(a) Subtotal†
–3·5 –2·3 –2·0 –2·0 –6·9 –6·5 –0·1 –6·1 –5·2
(1·2) (0·7) (2·0) (2·0) (7·5) (3·7) (1·2) (4·1) (7·1)
–34·6 (29·7) 69% (11) 2p<0·00001
Heterogeneity between nine trials: 2=12·0; p>0·1; 8
(b) 1–2 months before randomisation ± 12 months study treatment Coppen16 Doogan18 Feiger20 Montgomery38 Rouillon46 Versiani49
1·5 2 1·5 2 2 1·5
12 12 12 12 12 12
3/16 24/185 9/65 11/68 17/104 29/145
5/16 2 (48/110) 19/66 29/67 26/110 73/141
–1·0 (1·5) –21·2 (12·8) –4·9 (5·5) –9·1 (7·1) –3·9 (8·6) –22·7 (16·5)
93/583
248/620
–62·8 (52·0)
(b) Subtotal†
70% (8) 2p<0·00001
(16%)
(40%)
4/8 10/33 25/79
8/9 20/36 43/71
–1·6 –4·3 –10·8
39/120
71/116
–16·8 (14·6)
(33%)
(61%)
Heterogeneity between six trials: 2=9·1; p>0·1; 5
(c) 1–2 months before randomisation ± 18–36 months study treatment Glen23 OADIG39 Prien40
2 2 2
36 24 24
(c) Subtotal
(0·9) (4·3) (9·3)
68% (16) 2p<0·00001
Heterogeneity between three trials: 32=0·4; p>0·1; (d) 4–6 months before randomisation ± 12 months study treatment Georgotas (NTP)22 Georgotas (PHZ)22 Montgomery36 Rouillon45 Terra48
4 4 4 6 6
12 12 12 12 12
7/13 2/16 23/108 140/767 10/110
(d) Subtotal†
7/14 2 (8/9) 54/112 2 (120/374) 24/94
182/1014
341/986
(18%)
(35%)
0·3 (1·7) –4·4 (1·4) –14·8 (12·6) –34·8 (44·3) –8·3 (7·1) 60% (8) 2p<0·00001
–62·1 (67·1)
Heterogeneity between five trials: 2=10·7; p=0·03 4
(e) 4–6 months before randomisation ± 18–36 months study treatment Alexopoulos13 Frank (IPT)21 Frank21 Kane27 Keller28 Kishimoto29 Klysner31 Kocsis32 Reynolds42 Robinson44
4 4 4 6 6 4+ 3–4 4 4 4
24 36 36 24 18 18 36 18 36 24
(e) Subtotal*
4/22 6/25 6/28 5/14 11/77 4/12 19/60 4/28 17/53 9/31
11/21 17/26 18/23 8/13 34/84 13/14 41/61 12/25 42/54 2 (13/16)
–3·7 –5·3 –7·2 –1·7 –10·5 –3·8 –10·8 –4·5 –12·2 –5·5
(2·5) (3·2) (3·2) (1·7) (8·1) (1·5) (7·6) (2·8) (6·7) (2·7)
85/350
222/353
(24%)
(63%)
0/7 1/11
3/9 6/9
–1·3 –2·8
(0·6) (1·2)
1/18
9/18
–4·2
(1·8)
(6%)
(50%)
465/2527
1031/2505
80% (8) 2p<0·00001
–65·2 (40·2)
Heterogeneity between 10 trials: 29=5·2; p>0·1; 12+ months before randomisation ± 12 or 24 months study treatment Cook15 Kupfer33
12+ 36
12 24
(f) Subtotal
90% (29) 2p=0·002
Difference between treatment effects in two trials: 21=0·1; 2p>0·1; Total (a–f)
(18%) 99% or
–245·6
(205·4)
70% (4) 2p<0·00001
(41%)
95% confidence intervals 0
Heterogeneity between 35 trials: 2 =52·0; p=0·02 34
0·5
1·0
1·5
2·0
Antidepressant better Antidepressant worse Treatment effect 2p<0·00001
Figure 2: Odds ratios for relapse by duration of treatment before randomisation and duration of randomised treatment NTP=nortriptyline. PHZ=phenelzine. IPT=interpersonal psychotherapy. O–E=observed to expected ratio. *Duration of treatment after stabilisation. †Controls in 3-way trials count twice in subtotals, and in final total of events/patients.
THE LANCET • Vol 361 • February 22, 2003 • www.thelancet.com
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ARTICLES Diagnosis Alexopoulos Mixed first episode and 200013 recurrent RDC/DSM IV unipolar major depression Bialos RDC MDD (past history 198214† not stated) Cook 198615
Chart diagnosis of MDD with at least one previous episode
Coppen 197816
Mixed first and recurrent primary depressive illness of <18 months Feighner criteria nonbipolar definite depressive illness (past history unclear) Mixed first episode and recurrent unipolar and bipolar (<6%) DSM III MDD Recurrent DSM IIIR major depression
Davidson 198417 Doogan 199218 Eric 199119† Feiger 199920 Frank 199021
Georgotas 198922
Mixed first and recurrent DSM III R non-psychotic depressive disorder Recurrent RDC major depression
Mixed first and recurrent RDC unipolar MDD
Glen 198423
Primary depressive illness with one previous episode (Group 11)
Harrison 198624
DSM III R dysthymia (+/- MDD)
Medication before randomisation
Comparisons
Number in trial
Definition of relapse
16 weeks’ continuation of nortriptyline (plasma conc 60–150 g/L) Amitriptyline (50–250 mg) for an average of 3·7 years At least a year of desipramine, amitriptyline, doxepin, or imipramine 6 weeks’ continuation of amitripytline
Continuation of nortriptyline (plasma conc: 60–150 g/L) vs discontinuation* Continuation of same dose of amitriptyline vs discontinuation*
22 nortriptyline 21 placebo
RDC + DSM IV criteria for major depression and HDRS ⬎17 Depressive episode
24
Continuation of same dose of active medication vs discontinuation*
7 active treatment Change in drug treatment 9 placebo indicated
7
7 amitriptyline 10 placebo
Continuation of same dose of 16 amitriptyline amitriptyline vs discontinuation* 16 placebo
4 weeks’ continuation of Continuation of same dose of 9 phenelzine phenelzine 45–60 mg phenelzine vs discontinuation* 9 placebo 8 weeks’ treatment with Continuation of same dose of sertraline 50–200 mg sertraline vs discontinuation* 8 weeks’ treatment with paroxetine (dose not stated) 6 weeks’ continuation of nefazodone 100–600 mg 17 weeks’ continuation of imipramine (150–300 mg)
185 sertraline 110 placebo
Continuation of paroxetine 68 paroxetine (dose unclear) vs 67 placebo discontinuation* Continuation of nefazodone 65 nefazadone (dose unclear) vs 66 placebo discontinuation* (Five arm study) Continuation 25 imipramine of same dose of imipramine + 26 placebo IPT vs discontinuation* + IPT
Continuation of same dose of imipramine vs discontinuation to placebo At least 4 months’ Continuation of nortriptyline continuation of (plasma conc: nortriptyline (plasma 190–684 nmol/L) vs conc: 190–684 nmol/L) discontinuation* At least 4 months’ Continuation of phenelzine continuation of (platelet inhibition ⬎70%) phenelzine (platelet vs discontinuation* inhibition ⬎70%) Treatment at discretion (Three arm study) of treating psychiatrist Switched to amitriptyline (dose not stated) vs discontinuation* 6 week’ continuation of Continuation of same dose of phenelzine (mean dose phenelzine vs discontinuation* 57 mg)
12
CGI ⭓4
10
Not defined
12
5
HDRS ⭓18 on 8 two consecutive visits at least 7 days apart two RDC criteria for major depression 36 agreed by independent clinician
28 imipramine 23 placebo 13 nortripyline 14 placebo
RDC criteria and HDRS ⬎16
12
An affective episode of sufficient severity to require treatment other than night sedation CGI ⭓3 for two consecutive weeks
36
48–120‡
16 phenelzine 9 placebo
8 amitriptyline 9 placebo
5 phenelzine 7 placebo
16 weeks’ continuation Continuation of same dose of 132 citalopram with citalopram citalopram vs discontinuation* 137 placebo 20–60 mg
MADRS ⭓22 confirmed at 3–7 days
Jenkins 199026†
Mixed first episode and recurrent RDC MDD
6 week’ treatment with Continuation of same dose of gepirone (dose not gepirone vs discontinuation* stated)
36 gepirone 35 placebo
Kane 198227
Recurrent RDC unipolar depression
26 weeks’ treatment with imipramine 100–150 mg
14 imipramine 13 placebo
Keller 199828
Mixed first episode and recurrent but now chronic major depression of ⬎2 years and DSM III R dysthymia = major depression
28 weeks’ treatment with sertraline 50–200 mg
(Factorial design) Continuation of imipramine 100–150 mg with or without lithium vs discontiuation to placebo with or without lithium Continuation of same dose sertraline vs discontinuation*
Return to “no change” on CGI improvement or a return to 75% of baseline HDRS total score RDC for 7 days even with increased dose; or minor depressive disorder if symptoms persist for 4 weeks
Kishimoto 199429
Recurrent DSM III major depression
TCA at discretion of treating physician
12 mianserin 14 placebo
Klerman 197430
Primary depression of at least 2 weeks duration (criteria and past history not stated)
8 week’ continuation of amitriptyline 100–200 mg with psychotherapy
Switched to mianserin at approx 40% of previous TCA dose vs discontinuation* Continuation of amitriptyline 100–150 mg vs discontinuation*
Klysner 200031
DSM IV Major depression (past, history not stated)
12–16 weeks’ citalopram 20–40mg
656
6
Increase in symptoms sufficient to warrant hospital admission Change in drug treatment indicated or HDRS ⬎20
Hochstrasser Recurrent DSM IV 200125† major depression
Continuation of citalopram 20–40 mg vs discontinuation*
Follow-up (months)
77 sertraline 84 placebo
6
4‡
24
1) DSM III R criteria for MDD 18 for at least 3 weeks; 2) CGI severity score ⭓4; 3), CGI improvement score of ⭓3; 4) an increase in HDRS to a score of ⭓4 points higher than the maintenance phase baseline HDRS ⬎10 18
25 amitriptylline 25 placebo
Not defined
60 citalopram 61 placebo
MADRS ⭓22
6
48–120‡
THE LANCET • Vol 361 • February 22, 2003 • www.thelancet.com
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ARTICLES Kocsis 199632
Kupfer 199233
Lendresse 198534 Mindham 197335§
DSM III R dysthymia +/– current major depression or chronic subtype of major depression (past history not stated) Recurrent RDC major depression
Feighner major depressive state (past history not stated) Mixed first episode and recurrent MRC criteria primary depression
16 week continuation of desipramine 50–200 mg
Continuation of same dose of 28 desipramine desipramine vs discontinuation* 25 placebo
HDRS ⬎12 and GAS ⬍60 on three successive ratings over 4 weeks
4+36 months imipramine 150–300 mg (successful completers in Frank 199017 active treatment arms) 2 months’ treatment with up to 90 mg of nomifensine Up to 10 weeks’ treatment with amitriptyline (at least 150 mg)
Continuation of same dose of imipramine (150–300 mg) vs discontinuation*
11 imipramine 9 placebo
RDC criteria for major depression and HRSD ⭓15 and RSD ⭐7
(Three arm study) Continuation of nomifensine 75 mg vs discontinuation* Continuation of 75–150 mg amitriptyline vs discontinuation*
71 nomifensine 72 placebo
Not defined
6
34 amitriptyline 27 placebo
Depressive episode needing specific treatment (150 mg treatment, additional treatment, or ECT)
6
Continuation of 75–150mg imipramine vs discontinuation* 18 weeks’ continuation Continuation of fluoxetine of fluoxetine 40–80 mg 40 mg vs discontinuation*
Montgomery Recurrent DSM III major depression of at least 198836 moderate severity Montgomery DSM IIIR major depression 6 weeks’ treatment with (Three study arms) (past history not stated) citalopram 20 or 40 mg Continuation of same dose of 1993a37 citalopram vs discontinuation* Montgomery Recurrent DSM III R 8 weeks’ treatment with Continuation of 10 mg lower 38 unipolar MDD of moderate paroxetine 30–40 mg dose of paroxetine vs 1993b severity discontinuation*
OADIG 199339 Prien 198440
Mixed first episode and recurrent RDC depressive disorder RDC recurrent depression
Reimherr 199841†
Mixed first and recurrent DSM III R depressive disorder or bipolar II
Reynolds 199942§
Recurrent, non-psychotic, non-dysthymic unipolar major depression
Robert 199543
DSM III R MDD (past history not stated)
Robinson 199144
Recurrent RDC MDD
Rouillon 199145‡
Recurrent DSM III R MDD or dysthymia
Rouillon 200046
Recurrent DSM III R
Stein 198047†
Feighner Criteria MDD (past history not stated)
Terra 199848
Recurrent DSM III R MDD of at least moderate severity
Versiani 199949
Recurrent DSM III R MMD
Treatment at discretion of investigators with 8 continuation phase Initial treatment at discretion of psychiatrist and when stable treated for 8 weeks with imipramine 75–150 mg and lithium (0·6–0·9 mEq/L) 12–14 weeks’ treatment with fluoxetine 20 mg
Switched to dothiepin 75 mg vs placebo
(Factorial design) Continuation of same dose of imipramine +/– lithium/placebo vs discontinuation* +/- lithium/ placebo (Four arms study) Continuation of same dose of fluoxetine vs discontinuation to placebo at 0, 14, 38 weeks 16 week continuation (Factorial design) of nortriptyline (plasma Continuation of nortriptyline conc 80–120 g/L) within same range +/- IPT + IPT vs placebo +/- IPT 8 weeks’ treatment with Continuation of same dose of citalopram 20–60 mg citalopram vs discontinuation* 16 weeks’ continuation Continuation of phenelzine at of Phenelzine up to a dose of 45–60 vs 90 mg discontinuation to placebo 2 months’ treatment with (Four arm study) Continuation maprotiline 75–150 mg of maprotiline at dose of either 37·5 mg or 75 mg vs placebo 6 months’ continuation Continuation of same dose of of milnacipran 100 mg milnacipran or discontinuation* At least 8 weeks’ Continuation of 100–150 mg treatment with dose of amitriptyline vs amitriptyline, dose in discontinuation* final 2 weeks 100–150 mg 6 months treatment Continuation of fluvoxamine with fluvoxamine 100 mg vs discontinuation* tapered after 6 weeks’ to 100 mg 6 weeks’ treatment with Continuation of reboxetine reboxetine 8 mg 4–8 mg vs discontinuation*
16 imipramine 15 placebo 108 fluoxetine 112 placebo
105 citalopram 42 placebo 68 paroxetine 67 placebo
33 dothiepin 36 placebo
HDRS ⭓18
MADRS ⭓22 CGI ⭓4 or deterioration of CGI ⭓ 2 points since previous visit or DSM III R depression (without 2 weeks) or opinion of investigators need for antidepressants or depressive symptoms resent for ⬎7 days Clinical judgement or MADRS ⬎10
24
24
12
6 12
24
79 imipramine 71 placebo
RDC and GAS ⬍60
24
299 fluoxetine 96 placebo
DSM III R major depression or HDRS ⭓14 for 3 consecutive weeks
12
53 nortripyline 54 placebo
RDC and HDRS ⭓17 for ⭓2 weeks
36
152 citalopram 74 placebo
MADRS ⭓25 and clinical judgement
31 phenelzine 16 placebo
HDRS ⭓18 or raskin ⭓7 and GAS ⬍60
24
767 maprotiline 374 placebo
MADRS ⭓27 on 1 visit or MADRS ⭓25 on 2 visits or clinical judgment
12
104 milnacipran 110 placebo
DSM III R and HDRS ⭓18 and need for treatment
12
Not stated
Deterioration for 1–2 weeks despite increase in medication dose
6
110 fluvoxamine 94 placebo
DSM III R on two visits 8 days apart
12
145 reboxetine 141 placebo
Increase in HDRS by ⭓50% and or HDRS ⭓18
10
6
Details of how treatment allocation was concealed were unclear, unless otherwise stated. RDC=research diagnostic criteria. DSM=diagnostic and statistical manual. HDRS=Hamilton depression rating scale. CGI=clinical global impressions. MDD=major depressive disorder. MADR=Montgomery Asberg depression rating scale. IPT=Interpersonal psychotherapy. GAS=global assessment scale. MRC=Medical Research Council (UK). TCA=tricyclic antidepressant. ECT=electronconvulsive therapy. *Discontinuation to placebo. †Data not available. ‡Follow up in weeks. §Concealment of treatment allocation was judged to be adequate.
Characteristics of trials
THE LANCET • Vol 361 • February 22, 2003 • www.thelancet.com
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ARTICLES
Events/patients Placebo Allocated antidepressant adjusted
Antidepressant events Logrank (Variance O–E of O–E)
Odds ratio (95% CI) Antidepressant : Placebo
Reduction (SE)
(a) First recurrences 0–12 months after randomisation Frank (IPT)21 Frank (MC)21 Kupfer33 OADIG39 Reynolds42 Robinson44 (a) Subtotal*
2/25 5/28 0/11 8/33 13/53 7/31
12/26 15/23 5/9 19/36 31/54 2 (13/16)
–4·9 –6·0 –2·8 –4·9 –8·8 –6·2
(2·6) (3·1) (1·0) (4·2) (6·5) (2·6)
108/180 (60%)
–33·5
(20·0)
5/14 3/8 1/4 1/17 11/23 2 (0/3)
–1·6 –2·0 –0·5 –0·2 –5·5 –0·2
(1·6) (0·7) (0·4) (0·7) (2·7) (0·2)
14/146
21/72
–9·1
(6·3)
(10%)
(29%)
–42·6
(26·2)
35/181 (19%)
81% (11) 2p<0·00001
Heterogeneity between nine trials: 2=4·5; p>0·1; 5 (b) First recurrences 12–36 months after randomisation Frank (IPT)21 Frank (MC)21 Kupfer33 OADIG39 Reynolds42 Robinson44 (b) Subtotal*
4/23 1/23 1/11 2/25 4/40 2/24
77% (21) 2p=0·0003
Heterogeneity between six trials: 2= 6·2; p > 0·1 5
Total (a+b)*
49/327 (15%)
99% or
129/252
80% (10) 2p<0·00001
(51%)
95% confidence intervals 0
Heterogeneity between 12 trials:
2=10·9; 11
p>0·1
0·5
1·0
Antidepressant better
1·5
2·0
Antidepressant worse
Treatment effect 2p<0·00001 Figure 3: Efficacy of continuing antidepressant therapy in depressive disorder in different time periods of follow-up O–E=observed to expected ratio.*For balance, control patients in 3–way trials count twice in subtotals and in final total of events/patients. Trials are of 2–3 years of treatment, results during the first year of trial were available separately. At each time point the figure shows the number of patients who relapsed during that period the total number of patients who and remained at risk (ie, patients who had already relapsed in an earlier time period are excluded from the denominator).
calculated. For trials that had deliberately unbalanced treatment allocation, balance was restored by counting the control group more than once in these simple analyses.10 Odds ratios (with 95% CIs) were calculated with the fixed-effects method,11 and statistical heterogeneity between studies was tested for, to investigate whether individual trial results varied more than could be explained by chance alone. When significant heterogeneity was identified, possible causes were explored. Intention-to-treat data were used when available and, when not, the event rates provided in the published report were used. For the main analysis, trials were grouped in two ways. First, trials were classified according to the duration of treatment before randomisation (1–2 months, 4–6 months, or more than 12 months). We grouped trials in this way to investigate the possibility that the efficacy of continued antidepressant treatment might vary according to the duration of treatment before drug discontinuation.12 Second, trials were grouped by duration of randomised treatment (6, 12, or
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18–36 months) to assess whether continued treatment conferred further benefit. Hence, trials were categorised six ways for the purpose of the analysis. To investigate whether any treatment benefit was constant across time, the results during and after the first year were, where possible, analysed separately. In the second time period the number of patients who had already relapsed in the first year were excluded from the denominator. Role of the funding source The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit the paper for publication.
Results 122 reports and posters were identified as possibly satisfying the inclusion criteria. 33 studies, described in 40 publications, were excluded. Of these, ten were not randomised controlled trials, 21 were not of continuation
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% relapsed during trial
versus discontinuation design, one was a crossover study with no useable data, and in the remaining trial, participants had postpsychotic depression rather than a primary depressive disorder. 37 trials, described in 82 publications, satisfied the inclusion criteria (table).13–49 Data were not available from six of these trials.14,19,25,26,41,47 The quantitative analyses are therefore based on the results of 31 trials. In four of these trials21,22,30,35 where there were separately randomised strata, these were included separately in the analyses. Trials of most classes of antidepressant were identified, although most involved either a tricyclic antidepressant or a selective serotonin reuptake inhibitor (table). The trials included patients with a first episode and those recurrent disorders from various health-care settings (including both primary and secondary care). Seven trials17,24,30,34,35,37,43 (738 participants) provided information for 6 months’ follow-up; 1115,16,18,20,22,36,38,45,46,48,49 (2726 participants) at 12 months; three28,29,32 (240 participants) at 18 months; six13,27,33,39,40,44 (356 participants) at 24 months; and four21,23,31,42 (350 participants) at 36 months. Most therefore, were about trials of 12 months’ antidepressant therapy. Overall, results seemed similar for all classes of antidepressant (figure 1) and showed that continuing antidepressant therapy consistently reduced the risk of relapse (pooled odds ratio for relapse 0·30, 95% CI 0·22–0·38, 2p<0·00001; figure 2). The proportional risk reduction seemed to be similar in patients with shorter (1–2 months) and longer (4–6 months) treatment before randomisation and from 6 months to 36 months of randomised treatment (figure 2). There was statistically significant heterogeneity (234 52·0, p=0·02), between the trials, although inspection of the forest plots suggests that this heterogeneity is the result of quantitative rather than qualitative differences between trials. This odds ratio of 0·30 is roughly equivalent to a halving of the absolute risk of relapse: the average relapse rate on placebo was 41% compared with that on antidepressant of 19%. In the six trials of 2–3 years’ duration in which it was possible to obtain data about the number of patients relapsing in the first and subsequent years, the proportional risk reduction was similar in both periods (0–12 months, 81% reduction in odds: 12–36 months, 77% reduction in odds), although the absolute risk of relapse was twice as high in the first 12 months as it was in the subsequent 12–36 months (0–12 months control event rate 60%; 12–36 months event rate 29%; figure 3). There was no clear difference in either the treatment effect or the absolute risk of relapse in trials in which participants were randomised sooner (1–2 months) or later (4–6 months and ⭓12 months) after starting antidepressants (figures 2 and 4). For example, in trials with 1–2 months of prerandomisation treatment and 12 months’ follow-up, the average risk of relapse in the control group was 40%. In trials with 4–6 months of prerandomisation treatment and 12 months’ follow-up, the average risk of relapse in the control group was 35%. Findings were similar in trials with 2 years of randomised treatment (figure 4) More patients allocated to continue antidepressants than on placebo withdrew from the trials for reasons other than relapse or recurrence (active drug 18%, placebo 15%; OR 1·30, 95% CI 1·07–1·59; 2p=0·009). Only two trials reported data about suicide (five of 767 on maprotiline vs one of 374 controls,45 and one of 185 on sertraline vs none of 110 controls18). Even if all studies had reported data for this outcome, the numbers might not have been sufficient to yeild reliable results, since very
Allocated active antidepressant Allocated control
80 65 62
60 40
40
35
33 24
16
20
93 248 583 620
0 Duration of previous treatment
18 182 341 1014 986
1–2 months 4–6 months
Duration of +1 year treatment after randomisation
+1 year
43 84 132 130
81 209 338 339
1–2 months 4–6 months
+2 years
+2 years
Figure 4: Relapse rates after 1 or 2 years’ prolongation of antidepressant treatment in patients already treated for 1–2 or 4–6 months after an acute episode of depression
large-scale randomised evidence would probably be required to establish an effect on such an uncommon event.
Discussion On the basis of pooled results of 31 randomised trials that included 4410 patients, continuing treatment with antidepressants reduced the odds of depressive relapse by around two-thirds, which is approximately equivalent to a halving of the absolute risk. The treatment effect was similar across different classes of antidepressant. We are not aware of any previous methodologically satisfactory meta-analyses of these trials, although workers in a previous quantitative review of long-term antidepressant therapy reported a relative risk of relapse of 3·6 on drug discontinuation.50 Although the qualitative findings of the reviews are broadly equivalent, our review includes more trials and a formal meta-analysis that preserves the withinstudy randomised comparisons. The risk of relapse seemed similar across heterogeneous groups of patients including those who had recently responded to treatment of an acute episode of illness and those who had been successfully taking maintenance treatment for several months or even years. This finding is a clinically important simplification because current approaches to the treatment of depression try to distinguish between several stages in the recovery from depression and hypothesise different effects of treatment in each stage. In the current classification, response or partial remission refers to a clinically significant improvement; full remission occurs when symptoms have decreased to the extent that a reduction in intensity of treatment might be attempted; and recovery takes place when remission has lasted for a predefined period and discontinuation of treatment is being considered. This distinction between relapse and recurrence assumes that symptomatic improvement occurs before resolution of the underlying pathophysiology and that the risk of relapse decreases as the pathophysiology underlying the disorder resolves.12 Treatment is therefore divided into three stages: acute treatment phase, continuation therapy to prevent relapse,
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and maintenance therapy to prevent recurrence. Within the trials included in the review, however, there does not seem to be a clear distinction between the continuation and maintenance phase treatment effects. Several factors might limit the general applicability of our results. The trials were mainly done in secondary care settings, with patients at a high risk of relapse. This is an important patient group contributing substantially to the prevalence and burden of disease posed by major depression. How our results would apply to patients who were under-represented in the trials is unclear, particularly those with milder illnesses who might have a low underlying risk of relapse. There was heterogeneity in the risk of relapse in these patients in these trials and yet, in proportional terms, the effect of treatment was roughly equivalent, suggesting that even though the absolute effect in low-risk patients might be small, there might still be a benefit. This issue needs further investigation in future randomised trials. The trials were heterogeneous in terms of diagnostic criteria, drugs used, and criteria for relapse (table), but the consistent effect of treatment across trials suggests that the proportional risk reduction does not depend on such factors. Unavoidably, the design of the trials included in this review necessitated that some patients were withdrawn from active treatment. Therefore, the possiblity is raised that the risk of relapse or recurrence might be increased by a direct quasi-pharmacological response to the withdrawal of medication per se rather than the relapse or recurrence being solely due to the underlying disorder. This problem has been identified for lithium, for which acute withdrawal leads to manic relapse.51,52 Trials with a withdrawal design quite clearly inflated the apparent efficacy of lithium.53 In this review, there did not seem to be an excess of cases within a month of drug discontinuation as is the case with lithium,54 but we cannot exclude the possibility that there is a related effect. If there is an effect, the effectiveness of continuation therapy could have been overestimated. We relied on published reports of aggregate data, which meant that we were unable to do a survival analysis making full use of the time-to-relapse of individual patients. A meta-analysis using individual patient data is currently underway to investigate whether the observed relative risk reduction is constant across all patient subgroups, and to provide estimates of the absolute risk of relapse at particular time points and for specific subgroups of patients.55 The evidence suggests that many patients with recurrent depressive disorders who have responded well to acute phase treatment would benefit from continued treatment with antidepressants. The absolute benefit for any particular patient will depend on his or her underlying risk of relapse. High withdrawal rates in patients on antidepressants means that the treatment effect for compliant patients who can tolerate long-term medication might be even greater than that recorded in trials. Although the total number of patients followed for 12 months was substantial, relatively few trials reported follow-up of longer than 12 months, and further long-term trials are needed in representative patients, including those at low risk. Few other interventions in psychiatry are supported by such robust findings based on more than 4000 patients in randomised trials. We cannot make specific recommendations about which patients should or should not be offered long-term treatment with antidepressants, because treatment will depend on an individual patient’s baseline risk, a patient’s treatment preferences, and the clinician’s prior beliefs. However, for patients who are still at appreciable risk of recurrence after 4–6 months of
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treatment with antidepressants, another year (and probably more) of continuation treatment will approximately halve their risk. Contributors J Geddes initiated the review, contributed to data extraction, assessed the quality of studies, and did some of the analyses. He is the guarantor of the review. S Carney contributed to the design and writing of the protocol, managed the literature search, extracted data, and appraised study quality. C Davies extracted data, appraised study quality, and did some of the analyses. T Furukawa contributed to the design of the protocol, and appraised study quality. Guy Goodwin assessed study quality and contributed to the design and writing of the protocol. All authors helped to interpret findings and write the manuscript.
Conflict of interest statement None declared.
Acknowledgments We thank the Cochrane depression, anxiety, and neurosis group for their assistance with the literature search; Richard Peto and Jon Godwin of the Clinical Trial Service Unit for assistance with the analyses and preparation of the figures. Stuart Carney was funded by the Wellcome Trust during this study.
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19 Eric L. A prospective double-blind comparative multi-centre study of paroxetine in preventing recurrent major depressive episodes. Biol Psychiatry 1991; 29: 11–14. 20 Feiger AD, Bielski RJ, Bremner J, et al. Double-blind, placebosubstitution study of nefazodone in the prevention of relapse during continuation treatment of outpatients with major depression. Int Clin Psychopharmacol. 1999; 14: 19–28. 21 Frank E, Kupfer DJ, Perel JM, et al. Three-year outcomes for maintenance therapies in recurrent depression. Arch Gen Psychiatry 1990; 47: 1093–99. 22 Georgotas A, McCue RE, Cooper TB. A placebo-controlled comparison of nortriptyline and phenelzine in maintenance therapy of elderly depressed patients. Arch Gen Psychiatry 1989; 46: 783–86. 23 Glen AI, Johnson AL, Shepherd M. Continuation therapy with lithium and amitriptyline in unipolar depressive illness: a randomized, doubleblind, controlled trial. Psychol Med 1984; 14: 37–50. 24 Harrison W, Rabkin J, Stewart JW, et al. Phenelzine for chronic depression: a study of continuation treatment. J Clin Psychiatry 1986; 47: 346–49. 25 Hochstrasser B, Isaksen PM, Koponen H, et al. Prophylactic effect of citalopram in unipolar, recurrent depression: placebo-controlled study of maintenance therapy. Br J Psychiatry 2001; 178: 304–10 26 Jenkins SW, Robinson DS, Fabre LF. Gepirone treatment of major depression. J Clin Psychopharmacol 1991; 10: 77–85. 27 Kane JM, Quitkin FM, Rifkin A, Ramos L Jr, Nayak DD, Howard A. Lithium carbonate and imipramine in the prophylaxis of unipolar and bipolar II illness: a prospective, placebo-controlled comparison. Arch Gen Psychiatry 1982; 39: 1065–69. 28 Keller MB, Kocsis JH, Thase ME, et al. Maintenance phase efficacy of sertraline for chronic depression: a randomized controlled trial. JAMA 1998; 280: 1665–72. 29 Kishimoto A, Mizukawa R, Matsuzaki F, et al. Prophylactic effect of mianserin on recurrent depression. Acta Psychiatr Scand 1994; 89: 46–51. 30 Klerman GL, Dimascio A, Weissman M, Prusoff B, Paykel ES. Treatment of depression by drugs and psychotherapy. Am J Psychiatry 1974; 131: 186–91. 31 Klysner R, Bent-Hansen J, Hansen HL, et al. Efficacy of citalopram in the prevention of recurrent depression in elderly patients: placebocontrolled study of maintenance therapy. Br J Psychiatry 2002; 181: 29–35. 32 Kocsis JH, Friedman RA, Markowitz JC, et al. Maintenance therapy for chronic depression. A controlled clinical trial of desipramine. Arch Gen Psychiatry 1996; 53: 769–74. 33 Kupfer DJ, Frank E, Perel JM, et al. Five-year outcome for maintenance therapies in recurrent depression. Arch Gen Psychiatry 1992; 49: 769–73. 34 Lendresse PH, Chen MC, LeMarie JC. Traitement prolongé par nomifensine 75mg dans les états dépressifs neurotiques et reactionnels. Psychiatrie Francaise 1985; 16: 156–58. 35 Mindham RH, Howland C, Shepherd M. Continuation therapy with tricyclic antidepressants in depressive illness. Lancet 1972; 2: 854–55. 36 Montgomery SA, Dufour H, Brion S, et al. The prophylactic efficacy of fluoxetine in unipolar depression. Br J Psychiatry 1988; 3 (suppl): 69–76. 37 Montgomery SA, Rasmussen JG. Citalopram 20 mg, citalopram 40 mg and placebo in the prevention of relapse of major depression. Int Clin Psychopharmacol 1992; 6 (suppl 5): 71–73. 38 Montgomery SA, Dunbar G. Paroxetine is better than placebo in relapse
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prevention and the prophylaxis of recurrent depression. Int Clin Psychopharmacol 1993; 8: 189–95. Prien RF, Kupfer DJ, Mansky PA, et al. Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders. Report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine, and a lithium carbonate-imipramine combination. Arch Gen Psychiatry 1984; 41: 1096–104. Old Age Depression Interest Group. How long should the elderly take antidepressants? A double-blind placebo-controlled study of continuation/prophylaxis therapy with dothiepin. Br J Psychiatry 1993; 162: 175–82. Reimherr FW, Amsterdam JD, Quitkin FM, et al. Optimal length of continuation therapy in depression: a prospective assessment during long-term fluoxetine treatment. Am J Psychiatry 1998; 155: 1247–53. Reynolds CF, Frank E, Perel JM, et al. Nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression: a randomized controlled trial in patients older than 59 years. JAMA 1999; 281: 39–45. Robert P, Montgomery SA. Citalopram in doses of 20–60 mg is effective in depression relapse prevention: a placebo-controlled 6 month study. Int Clin Psychopharmacol 1995; 10 (suppl 1): 29–35. Robinson DS, Lerfald SC, Bennett B, et al. Continuation and maintenance treatment of major depression with the monoamine oxidase inhibitor phenelzine: a double-blind placebo-controlled discontinuation study. Psychopharmacol Bull 1991; 27: 31–39. Rouillon F, Phillips R, Serrurier D, Ansart E, Gerard MJ. Rechutes de dépression unipolaire et efficacité de la maprotiline. Encephale 1989; 15: 527–34. Rouillon F, Berdeaux G, Bisserbe JC, et al. Prevention of recurrent depressive episodes with milnacipran: consequences on quality of life. J Affect Disord 2000; 58: 171–80. Stein MK, Rickels K, Weise CC. Maintenance therapy with amitriptyline: a controlled trial. Am J Psychiatry 1980; 137: 370–71. Terra JL, Montgomery SA. Fluvoxamine prevents recurrence of depression: results of a long-term, double-blind, placebo-controlled study. Int Clin Psychopharmacol 1998; 13: 55–62. Versiani M, Mehilane L, Gaszner P, Arnaud CR. Reboxetine, a unique selective NRI, prevents relapse and recurrence in long-term treatment of major depressive disorder. J Clin Psychiatry 1999; 60: 400–06. Viguera AC, Baldessarini RJ, Friedberg J. Discontinuing antidepressant treatment in major depression. Harv Rev Psychiatry 1998; 5: 293–306. Goodwin GM. Recurrence of mania after lithium withdrawal. Implications for the use of lithium in the treatment of bipolar affective disorder. Br J Psychiatry 1994; 164: 149–52. Suppes T, Baldessarini RJ, Faedda GL, Tohen M. Risk of recurrence following discontinuation of lithium treatment in bipolar disorder. Arch Gen Psychiatry 1991; 48: 1082–88. Burgess S, Geddes JR, Townsend E, Jamison K, Hawton K, Goodwin GM. Lithium for maintenance treatment of mood disorders. Cochrane Database Syst Rev 2001; (3): CD003013. Mander AJ, Loudon JB. Rapid recurrence of mania following abrupt discontinuation of lithium. Lancet 1988; 2: 15–17. Clarke MJ, Stewart LA. Obtaining data from randomised controlled trials: how much do we need for reliable and informative meta-analyses? BMJ 1994; 309: 1007–10.
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Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review
John R Geddes, Stuart M Carney, Christina Davies, Toshiaki A Furukawa, David J Kupfer, Ellen Frank, Guy M Goodwin
Summary Background Antidepressant drugs can promote remission from acute depressive episodes. Our aim was to establish how long such treatments should be continued to prevent relapse. Method We did a systematic overview of evidence from randomised trials of continuing treatment with antidepressants in patients with depressive disorders who have responded to acute treatment. Medline, Embase, Cinahl, PsycLIT, Psyndex, and Lilacs were searched. Findings Data were pooled from 31 randomised trials (4410 participants). Continuing treatment with antidepressants reduced the odds of relapse by 70% (95% CI 62–78; 2p<0·00001) compared with treatment discontinuation. The average rate of relapse on placebo was 41% compared with 18% on active treatment. The treatment effect seemed to persist for up to 36 months, although most trials were of 12 months’ duration, and so the evidence on longer-term treatment requires confirmation. Significantly more participants allocated antidepressants withdrew from the trials than did those allocated to placebo (18% vs 15%, respectively; odds ratio 1·30, 95% CI 1·07–1·59): the treatment effect could be even greater in adherent patients. The two-thirds reduction in risk of depressive relapse seemed to be largely independent of the underlying risk of relapse, the duration of treatment before randomisation, or the duration of the randomly allocated therapy. Interpretation Antidepressants reduce the risk of relapse in depressive disorder, and continued treatment with antidepressants would benefit many patients with recurrent depressive disorder. The treatment benefit for an individual patient will depend on their absolute risk of relapse with greater absolute benefits in those at higher risk. Further trials are needed to establish the optimum length of therapy and should include patients who were not well represented in these trials, including those at low risk of relapse. Lancet 2003; 361: 653–51
Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK (Prof J R Geddes MD, S M Carney MRCPsych, Prof G M Goodwin FRCPsych); Clinical Trial Service Unit, University of Oxford, Radcliffe Infirmary, Oxford (C Davies MBChB); Department of Psychiatry, Nagoya City University Medical School, Mizuho-cho, Mizuho-ku, Nagoya, Japan (Prof T A Furukawa MD); and Department of Psychiatry, UPMC Health System, Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA (Prof D J Kupfer MD, Prof E Frank PhD) Correspondence to: Prof John Geddes, University of Oxford, Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX, UK. (e-mail: [email protected])
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Introduction Neuropsychiatric illnesses in general and unipolar depressive disorder in particular are among the most important causes of death and disability worldwide, in both developing and developed countries.1,2 Short-term and medium-term therapy with antidepressant drugs is already standard treatment for acute episodes of depression.3 However, because of the long-term nature of depressive disorder, with many patients at substantial risk of later recurrence, there is a considerable need to establish how long, in general, such patients should stay on antidepressants. Clinical guidelines recommend that treatment should be continued for 4–6 months after the acute episode (panel). However, there is considerable variation in practice, suggesting that many patients do not receive optimum treatment.8 We aimed systematically to review evidence from randomised trials to determine whether continuing treatment with antidepressants reduces the risk of relapse (ie, a return of symptoms during a period of remission or partial remission) or recurrence (ie, a new episode during a period of recovery) of depressive symptoms. In addition, we assessed whether the magnitude of this benefit varies according to the length of previous treatment, length of continuing treatment, and the underlying level of risk of relapse.
Methods Data acquisition The aim of this systematic review was to identify all randomised trials, published or unpublished, available for review by August, 2000, in which continued antidepressant drug therapy was compared with placebo in patients who had responded to acute treatment with antidepressants.
Search strategy Electronic databases The Cochrane collaboration depression, anxiety, and neurosis controlled trials register (CCDANCTR), which incorporates results of group searches of Medline (1966, to April, 2000); Embase (1980, to April, 2000); Cinahl (1982, to April, 2000); PsycLIT (1974, to April, 2000); Psyndex (1977, to December, 1999); and Lilacs (1982, to December, 1999) were searched with the following terms: #45 (diagnosis field)=depression* or depressive-disorder or dysthymi* and (maintenance* or maintain* or continu* or preventive) and #30 (intervention field)=pharmacotherapy.* The Cochrane controlled trials register was searched with the same terms as for CCDANCTR, but excluded references tagged with sr-depress* because they were already obtained from CCDANCTR. Reference checking the reference lists of all selected studies were inspected for additional published reports and citations of unpublished research. Other relevant papers and major textbooks that cover mood disorder were checked. Personal communications authors of identified papers, experts in the field, and drug companies that manufacture antidepressants were contacted
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Guidelines for duration of antidepressant treatment after acute treatment response Recommended duration of continuation* after medical management of the acute episode (months)
Number of episodes that would indicate longer "maintenance" treatment is appropriate
UK defeat depression consensus statement4
4–6
⭓2
US Agency for Health Care Policy and Research5
4–9
⭓3
British Association for Psychopharmacology6
6
⭓3 in past 5 years (or ⭓6 in total)
American Psychiatric Association7
4–5
Not specified
Quality assessment Two reviewers (TF and GG) assessed independently the methodological quality of eligible trials. A qualitative assessment was made by investigation of those aspects of trial design generally considered to be most crucial for internal validity—namely, methods of randomisation and prior concealment of treatment allocation from investigators and patients; masking the identity of the randomly allocated treatment from the investigator and participant (for example, by use of a placebo control); masking the allocated treatment from the outcome assessor; reporting withdrawals and dropouts; and the method of analysis (intention-to-treat analyses were judged clinically most useful and more statistically robust than other types of analysis). If adequate details of these characteristics of trials were not provided in the published reports of the trials, we contacted the authors to obtain further information.
Trials in which patients were randomly allocated treatment after acute treatment response were included, along with those in which patients were randomised after a variable period of continuing therapy.
Data extraction Two reviewers (SC and CD) extracted data about participants’ characteristics, intervention details (including whether or not the study was of a discontinuation design), and outcome measures from the included studies. A further reviewer (JG) checked the data. Data were entered into review manager software (version 4.1). Relapse or recurrence was counted according to the original authors’ definitions.
Selection of trials The search results were checked independently by two reviewers (SC and JG) and all potentially suitable studies were requested. SC and CD checked independently all identified studies. Any disagreements as to whether a study should be included were resolved by discussion with a third member (JG). Trials were eligible for the review if: (1) they included patients with depressive disorders who had either responded to treatment for an acute episode, or who had remained free from depressive illness for a period on antidepressants following initial response to treatment; and (2) patients were then randomly allocated to continue or discontinue treatment and were followed up for a minimum of 1 month.
Data analysis The published reports did not provide enough information to allow a meta-analysis of time-to-relapse data. We therefore used tabulated data on total relapse rates at a specific point after randomisation. Both relative and absolute treatment effects were calculated. The relative effects of treatment (eg, a halving of risk) might well be more generalisable than the absolute effects,9 but the absolute effects are more directly relevant to helping clinicians make informed treatment decisions in specific clinical situations. In the simplest summaries of overall trial results, all treatment and control groups were added together and the proportions of patients relapsing in each group were
*At same dose.
Number of trials NARI
2
MAOI
4
Tricyclic
15
SSRI
10
Other
1
Total
99% or
32
Events/patients Allocated Placebo antidepressant adjusted 169/912 (19%) 13/61 (21%) 113/449 (25%) 156/1034 (15%) 14/71 (20%)
313/889 (35%) 57/66 (86%) 248/432 (57%) 385/1046 (37%) 28/72 (39%)
465/ 2527 (18%)
1031/ 2505 (41%)
Antidepressant events Logrank (Variance O–E of O–E) –57·5
(60·7)
–15·7
(6·0)
–70·7
(50·5)
–94·9
(80·7)
–6·9
(7·5)
–245·7
(205·4)
Odds ratio (95% CI) Antidepressant : Placebo
Reduction (SE)
70% (4) 2p<0·00001
95% confidence intervals 0
Heterogeneity between five categories: 24=18·6; p=0·001
0·5 1·0 1·5 2·0 Antidepressant better Antidepressant worse Treatment effect 2p<0·00001
Figure 1: Risk of relapse: odds ratios by drug type NARI=noradrenaline (norepinephrine) reuptake inhibitor. MAOI=monoamine oxidase inhibitor. SSRI=selective serotonin reuptake inhibitor.
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Months of treatment Prerandomised* Randomised
Events/patients Adjusted Allocated placebo antidepressant
Antidepressant events Logrank (Variance O–E of O–E)
Odds ratio (95%) Antidepressant : Placebo
Reduction (SE)
(a) 1–2 months before randomisation ± 6 months study treatment Davidson17 Harrison24 Klerman30 Klerman30 Lendresse34 Mindham35 Mindham35 Montgomery37 Robert43
1 1·5 2 2 2 2 2 1·5 2
6 6 6 6 6 6 6 6 6
1/9 1/5 3/25 3/25 14/71 8/34 3/16 11/105 21/152
8/9 7/7 7/25 7/25 28/72 18/27 3/15 2 (13/42) 2 (18/74)
65/442
140/412
(15%)
(34%)
(a) Subtotal†
–3·5 –2·3 –2·0 –2·0 –6·9 –6·5 –0·1 –6·1 –5·2
(1·2) (0·7) (2·0) (2·0) (7·5) (3·7) (1·2) (4·1) (7·1)
–34·6 (29·7) 69% (11) 2p<0·00001
Heterogeneity between nine trials: 2=12·0; p>0·1; 8
(b) 1–2 months before randomisation ± 12 months study treatment Coppen16 Doogan18 Feiger20 Montgomery38 Rouillon46 Versiani49
1·5 2 1·5 2 2 1·5
12 12 12 12 12 12
3/16 24/185 9/65 11/68 17/104 29/145
5/16 2 (48/110) 19/66 29/67 26/110 73/141
–1·0 (1·5) –21·2 (12·8) –4·9 (5·5) –9·1 (7·1) –3·9 (8·6) –22·7 (16·5)
93/583
248/620
–62·8 (52·0)
(b) Subtotal†
70% (8) 2p<0·00001
(16%)
(40%)
4/8 10/33 25/79
8/9 20/36 43/71
–1·6 –4·3 –10·8
39/120
71/116
–16·8 (14·6)
(33%)
(61%)
Heterogeneity between six trials: 2=9·1; p>0·1; 5
(c) 1–2 months before randomisation ± 18–36 months study treatment Glen23 OADIG39 Prien40
2 2 2
36 24 24
(c) Subtotal
(0·9) (4·3) (9·3)
68% (16) 2p<0·00001
Heterogeneity between three trials: 32=0·4; p>0·1; (d) 4–6 months before randomisation ± 12 months study treatment Georgotas (NTP)22 Georgotas (PHZ)22 Montgomery36 Rouillon45 Terra48
4 4 4 6 6
12 12 12 12 12
7/13 2/16 23/108 140/767 10/110
(d) Subtotal†
7/14 2 (8/9) 54/112 2 (120/374) 24/94
182/1014
341/986
(18%)
(35%)
0·3 (1·7) –4·4 (1·4) –14·8 (12·6) –34·8 (44·3) –8·3 (7·1) 60% (8) 2p<0·00001
–62·1 (67·1)
Heterogeneity between five trials: 2=10·7; p=0·03 4
(e) 4–6 months before randomisation ± 18–36 months study treatment Alexopoulos13 Frank (IPT)21 Frank21 Kane27 Keller28 Kishimoto29 Klysner31 Kocsis32 Reynolds42 Robinson44
4 4 4 6 6 4+ 3–4 4 4 4
24 36 36 24 18 18 36 18 36 24
(e) Subtotal*
4/22 6/25 6/28 5/14 11/77 4/12 19/60 4/28 17/53 9/31
11/21 17/26 18/23 8/13 34/84 13/14 41/61 12/25 42/54 2 (13/16)
–3·7 –5·3 –7·2 –1·7 –10·5 –3·8 –10·8 –4·5 –12·2 –5·5
(2·5) (3·2) (3·2) (1·7) (8·1) (1·5) (7·6) (2·8) (6·7) (2·7)
85/350
222/353
(24%)
(63%)
0/7 1/11
3/9 6/9
–1·3 –2·8
(0·6) (1·2)
1/18
9/18
–4·2
(1·8)
(6%)
(50%)
465/2527
1031/2505
80% (8) 2p<0·00001
–65·2 (40·2)
Heterogeneity between 10 trials: 29=5·2; p>0·1; 12+ months before randomisation ± 12 or 24 months study treatment Cook15 Kupfer33
12+ 36
12 24
(f) Subtotal
90% (29) 2p=0·002
Difference between treatment effects in two trials: 21=0·1; 2p>0·1; Total (a–f)
(18%) 99% or
–245·6
(205·4)
70% (4) 2p<0·00001
(41%)
95% confidence intervals 0
Heterogeneity between 35 trials: 2 =52·0; p=0·02 34
0·5
1·0
1·5
2·0
Antidepressant better Antidepressant worse Treatment effect 2p<0·00001
Figure 2: Odds ratios for relapse by duration of treatment before randomisation and duration of randomised treatment NTP=nortriptyline. PHZ=phenelzine. IPT=interpersonal psychotherapy. O–E=observed to expected ratio. *Duration of treatment after stabilisation. †Controls in 3-way trials count twice in subtotals, and in final total of events/patients.
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For personal use. Only reproduce with permission from The Lancet Publishing Group.
ARTICLES Diagnosis Alexopoulos Mixed first episode and 200013 recurrent RDC/DSM IV unipolar major depression Bialos RDC MDD (past history 198214† not stated) Cook 198615
Chart diagnosis of MDD with at least one previous episode
Coppen 197816
Mixed first and recurrent primary depressive illness of <18 months Feighner criteria nonbipolar definite depressive illness (past history unclear) Mixed first episode and recurrent unipolar and bipolar (<6%) DSM III MDD Recurrent DSM IIIR major depression
Davidson 198417 Doogan 199218 Eric 199119† Feiger 199920 Frank 199021
Georgotas 198922
Mixed first and recurrent DSM III R non-psychotic depressive disorder Recurrent RDC major depression
Mixed first and recurrent RDC unipolar MDD
Glen 198423
Primary depressive illness with one previous episode (Group 11)
Harrison 198624
DSM III R dysthymia (+/- MDD)
Medication before randomisation
Comparisons
Number in trial
Definition of relapse
16 weeks’ continuation of nortriptyline (plasma conc 60–150 g/L) Amitriptyline (50–250 mg) for an average of 3·7 years At least a year of desipramine, amitriptyline, doxepin, or imipramine 6 weeks’ continuation of amitripytline
Continuation of nortriptyline (plasma conc: 60–150 g/L) vs discontinuation* Continuation of same dose of amitriptyline vs discontinuation*
22 nortriptyline 21 placebo
RDC + DSM IV criteria for major depression and HDRS ⬎17 Depressive episode
24
Continuation of same dose of active medication vs discontinuation*
7 active treatment Change in drug treatment 9 placebo indicated
7
7 amitriptyline 10 placebo
Continuation of same dose of 16 amitriptyline amitriptyline vs discontinuation* 16 placebo
4 weeks’ continuation of Continuation of same dose of 9 phenelzine phenelzine 45–60 mg phenelzine vs discontinuation* 9 placebo 8 weeks’ treatment with Continuation of same dose of sertraline 50–200 mg sertraline vs discontinuation* 8 weeks’ treatment with paroxetine (dose not stated) 6 weeks’ continuation of nefazodone 100–600 mg 17 weeks’ continuation of imipramine (150–300 mg)
185 sertraline 110 placebo
Continuation of paroxetine 68 paroxetine (dose unclear) vs 67 placebo discontinuation* Continuation of nefazodone 65 nefazadone (dose unclear) vs 66 placebo discontinuation* (Five arm study) Continuation 25 imipramine of same dose of imipramine + 26 placebo IPT vs discontinuation* + IPT
Continuation of same dose of imipramine vs discontinuation to placebo At least 4 months’ Continuation of nortriptyline continuation of (plasma conc: nortriptyline (plasma 190–684 nmol/L) vs conc: 190–684 nmol/L) discontinuation* At least 4 months’ Continuation of phenelzine continuation of (platelet inhibition ⬎70%) phenelzine (platelet vs discontinuation* inhibition ⬎70%) Treatment at discretion (Three arm study) of treating psychiatrist Switched to amitriptyline (dose not stated) vs discontinuation* 6 week’ continuation of Continuation of same dose of phenelzine (mean dose phenelzine vs discontinuation* 57 mg)
12
CGI ⭓4
10
Not defined
12
5
HDRS ⭓18 on 8 two consecutive visits at least 7 days apart two RDC criteria for major depression 36 agreed by independent clinician
28 imipramine 23 placebo 13 nortripyline 14 placebo
RDC criteria and HDRS ⬎16
12
An affective episode of sufficient severity to require treatment other than night sedation CGI ⭓3 for two consecutive weeks
36
48–120‡
16 phenelzine 9 placebo
8 amitriptyline 9 placebo
5 phenelzine 7 placebo
16 weeks’ continuation Continuation of same dose of 132 citalopram with citalopram citalopram vs discontinuation* 137 placebo 20–60 mg
MADRS ⭓22 confirmed at 3–7 days
Jenkins 199026†
Mixed first episode and recurrent RDC MDD
6 week’ treatment with Continuation of same dose of gepirone (dose not gepirone vs discontinuation* stated)
36 gepirone 35 placebo
Kane 198227
Recurrent RDC unipolar depression
26 weeks’ treatment with imipramine 100–150 mg
14 imipramine 13 placebo
Keller 199828
Mixed first episode and recurrent but now chronic major depression of ⬎2 years and DSM III R dysthymia = major depression
28 weeks’ treatment with sertraline 50–200 mg
(Factorial design) Continuation of imipramine 100–150 mg with or without lithium vs discontiuation to placebo with or without lithium Continuation of same dose sertraline vs discontinuation*
Return to “no change” on CGI improvement or a return to 75% of baseline HDRS total score RDC for 7 days even with increased dose; or minor depressive disorder if symptoms persist for 4 weeks
Kishimoto 199429
Recurrent DSM III major depression
TCA at discretion of treating physician
12 mianserin 14 placebo
Klerman 197430
Primary depression of at least 2 weeks duration (criteria and past history not stated)
8 week’ continuation of amitriptyline 100–200 mg with psychotherapy
Switched to mianserin at approx 40% of previous TCA dose vs discontinuation* Continuation of amitriptyline 100–150 mg vs discontinuation*
Klysner 200031
DSM IV Major depression (past, history not stated)
12–16 weeks’ citalopram 20–40mg
656
6
Increase in symptoms sufficient to warrant hospital admission Change in drug treatment indicated or HDRS ⬎20
Hochstrasser Recurrent DSM IV 200125† major depression
Continuation of citalopram 20–40 mg vs discontinuation*
Follow-up (months)
77 sertraline 84 placebo
6
4‡
24
1) DSM III R criteria for MDD 18 for at least 3 weeks; 2) CGI severity score ⭓4; 3), CGI improvement score of ⭓3; 4) an increase in HDRS to a score of ⭓4 points higher than the maintenance phase baseline HDRS ⬎10 18
25 amitriptylline 25 placebo
Not defined
60 citalopram 61 placebo
MADRS ⭓22
6
48–120‡
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ARTICLES Kocsis 199632
Kupfer 199233
Lendresse 198534 Mindham 197335§
DSM III R dysthymia +/– current major depression or chronic subtype of major depression (past history not stated) Recurrent RDC major depression
Feighner major depressive state (past history not stated) Mixed first episode and recurrent MRC criteria primary depression
16 week continuation of desipramine 50–200 mg
Continuation of same dose of 28 desipramine desipramine vs discontinuation* 25 placebo
HDRS ⬎12 and GAS ⬍60 on three successive ratings over 4 weeks
4+36 months imipramine 150–300 mg (successful completers in Frank 199017 active treatment arms) 2 months’ treatment with up to 90 mg of nomifensine Up to 10 weeks’ treatment with amitriptyline (at least 150 mg)
Continuation of same dose of imipramine (150–300 mg) vs discontinuation*
11 imipramine 9 placebo
RDC criteria for major depression and HRSD ⭓15 and RSD ⭐7
(Three arm study) Continuation of nomifensine 75 mg vs discontinuation* Continuation of 75–150 mg amitriptyline vs discontinuation*
71 nomifensine 72 placebo
Not defined
6
34 amitriptyline 27 placebo
Depressive episode needing specific treatment (150 mg treatment, additional treatment, or ECT)
6
Continuation of 75–150mg imipramine vs discontinuation* 18 weeks’ continuation Continuation of fluoxetine of fluoxetine 40–80 mg 40 mg vs discontinuation*
Montgomery Recurrent DSM III major depression of at least 198836 moderate severity Montgomery DSM IIIR major depression 6 weeks’ treatment with (Three study arms) (past history not stated) citalopram 20 or 40 mg Continuation of same dose of 1993a37 citalopram vs discontinuation* Montgomery Recurrent DSM III R 8 weeks’ treatment with Continuation of 10 mg lower 38 unipolar MDD of moderate paroxetine 30–40 mg dose of paroxetine vs 1993b severity discontinuation*
OADIG 199339 Prien 198440
Mixed first episode and recurrent RDC depressive disorder RDC recurrent depression
Reimherr 199841†
Mixed first and recurrent DSM III R depressive disorder or bipolar II
Reynolds 199942§
Recurrent, non-psychotic, non-dysthymic unipolar major depression
Robert 199543
DSM III R MDD (past history not stated)
Robinson 199144
Recurrent RDC MDD
Rouillon 199145‡
Recurrent DSM III R MDD or dysthymia
Rouillon 200046
Recurrent DSM III R
Stein 198047†
Feighner Criteria MDD (past history not stated)
Terra 199848
Recurrent DSM III R MDD of at least moderate severity
Versiani 199949
Recurrent DSM III R MMD
Treatment at discretion of investigators with 8 continuation phase Initial treatment at discretion of psychiatrist and when stable treated for 8 weeks with imipramine 75–150 mg and lithium (0·6–0·9 mEq/L) 12–14 weeks’ treatment with fluoxetine 20 mg
Switched to dothiepin 75 mg vs placebo
(Factorial design) Continuation of same dose of imipramine +/– lithium/placebo vs discontinuation* +/- lithium/ placebo (Four arms study) Continuation of same dose of fluoxetine vs discontinuation to placebo at 0, 14, 38 weeks 16 week continuation (Factorial design) of nortriptyline (plasma Continuation of nortriptyline conc 80–120 g/L) within same range +/- IPT + IPT vs placebo +/- IPT 8 weeks’ treatment with Continuation of same dose of citalopram 20–60 mg citalopram vs discontinuation* 16 weeks’ continuation Continuation of phenelzine at of Phenelzine up to a dose of 45–60 vs 90 mg discontinuation to placebo 2 months’ treatment with (Four arm study) Continuation maprotiline 75–150 mg of maprotiline at dose of either 37·5 mg or 75 mg vs placebo 6 months’ continuation Continuation of same dose of of milnacipran 100 mg milnacipran or discontinuation* At least 8 weeks’ Continuation of 100–150 mg treatment with dose of amitriptyline vs amitriptyline, dose in discontinuation* final 2 weeks 100–150 mg 6 months treatment Continuation of fluvoxamine with fluvoxamine 100 mg vs discontinuation* tapered after 6 weeks’ to 100 mg 6 weeks’ treatment with Continuation of reboxetine reboxetine 8 mg 4–8 mg vs discontinuation*
16 imipramine 15 placebo 108 fluoxetine 112 placebo
105 citalopram 42 placebo 68 paroxetine 67 placebo
33 dothiepin 36 placebo
HDRS ⭓18
MADRS ⭓22 CGI ⭓4 or deterioration of CGI ⭓ 2 points since previous visit or DSM III R depression (without 2 weeks) or opinion of investigators need for antidepressants or depressive symptoms resent for ⬎7 days Clinical judgement or MADRS ⬎10
24
24
12
6 12
24
79 imipramine 71 placebo
RDC and GAS ⬍60
24
299 fluoxetine 96 placebo
DSM III R major depression or HDRS ⭓14 for 3 consecutive weeks
12
53 nortripyline 54 placebo
RDC and HDRS ⭓17 for ⭓2 weeks
36
152 citalopram 74 placebo
MADRS ⭓25 and clinical judgement
31 phenelzine 16 placebo
HDRS ⭓18 or raskin ⭓7 and GAS ⬍60
24
767 maprotiline 374 placebo
MADRS ⭓27 on 1 visit or MADRS ⭓25 on 2 visits or clinical judgment
12
104 milnacipran 110 placebo
DSM III R and HDRS ⭓18 and need for treatment
12
Not stated
Deterioration for 1–2 weeks despite increase in medication dose
6
110 fluvoxamine 94 placebo
DSM III R on two visits 8 days apart
12
145 reboxetine 141 placebo
Increase in HDRS by ⭓50% and or HDRS ⭓18
10
6
Details of how treatment allocation was concealed were unclear, unless otherwise stated. RDC=research diagnostic criteria. DSM=diagnostic and statistical manual. HDRS=Hamilton depression rating scale. CGI=clinical global impressions. MDD=major depressive disorder. MADR=Montgomery Asberg depression rating scale. IPT=Interpersonal psychotherapy. GAS=global assessment scale. MRC=Medical Research Council (UK). TCA=tricyclic antidepressant. ECT=electronconvulsive therapy. *Discontinuation to placebo. †Data not available. ‡Follow up in weeks. §Concealment of treatment allocation was judged to be adequate.
Characteristics of trials
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ARTICLES
Events/patients Placebo Allocated antidepressant adjusted
Antidepressant events Logrank (Variance O–E of O–E)
Odds ratio (95% CI) Antidepressant : Placebo
Reduction (SE)
(a) First recurrences 0–12 months after randomisation Frank (IPT)21 Frank (MC)21 Kupfer33 OADIG39 Reynolds42 Robinson44 (a) Subtotal*
2/25 5/28 0/11 8/33 13/53 7/31
12/26 15/23 5/9 19/36 31/54 2 (13/16)
–4·9 –6·0 –2·8 –4·9 –8·8 –6·2
(2·6) (3·1) (1·0) (4·2) (6·5) (2·6)
108/180 (60%)
–33·5
(20·0)
5/14 3/8 1/4 1/17 11/23 2 (0/3)
–1·6 –2·0 –0·5 –0·2 –5·5 –0·2
(1·6) (0·7) (0·4) (0·7) (2·7) (0·2)
14/146
21/72
–9·1
(6·3)
(10%)
(29%)
–42·6
(26·2)
35/181 (19%)
81% (11) 2p<0·00001
Heterogeneity between nine trials: 2=4·5; p>0·1; 5 (b) First recurrences 12–36 months after randomisation Frank (IPT)21 Frank (MC)21 Kupfer33 OADIG39 Reynolds42 Robinson44 (b) Subtotal*
4/23 1/23 1/11 2/25 4/40 2/24
77% (21) 2p=0·0003
Heterogeneity between six trials: 2= 6·2; p > 0·1 5
Total (a+b)*
49/327 (15%)
99% or
129/252
80% (10) 2p<0·00001
(51%)
95% confidence intervals 0
Heterogeneity between 12 trials:
2=10·9; 11
p>0·1
0·5
1·0
Antidepressant better
1·5
2·0
Antidepressant worse
Treatment effect 2p<0·00001 Figure 3: Efficacy of continuing antidepressant therapy in depressive disorder in different time periods of follow-up O–E=observed to expected ratio.*For balance, control patients in 3–way trials count twice in subtotals and in final total of events/patients. Trials are of 2–3 years of treatment, results during the first year of trial were available separately. At each time point the figure shows the number of patients who relapsed during that period the total number of patients who and remained at risk (ie, patients who had already relapsed in an earlier time period are excluded from the denominator).
calculated. For trials that had deliberately unbalanced treatment allocation, balance was restored by counting the control group more than once in these simple analyses.10 Odds ratios (with 95% CIs) were calculated with the fixed-effects method,11 and statistical heterogeneity between studies was tested for, to investigate whether individual trial results varied more than could be explained by chance alone. When significant heterogeneity was identified, possible causes were explored. Intention-to-treat data were used when available and, when not, the event rates provided in the published report were used. For the main analysis, trials were grouped in two ways. First, trials were classified according to the duration of treatment before randomisation (1–2 months, 4–6 months, or more than 12 months). We grouped trials in this way to investigate the possibility that the efficacy of continued antidepressant treatment might vary according to the duration of treatment before drug discontinuation.12 Second, trials were grouped by duration of randomised treatment (6, 12, or
658
18–36 months) to assess whether continued treatment conferred further benefit. Hence, trials were categorised six ways for the purpose of the analysis. To investigate whether any treatment benefit was constant across time, the results during and after the first year were, where possible, analysed separately. In the second time period the number of patients who had already relapsed in the first year were excluded from the denominator. Role of the funding source The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit the paper for publication.
Results 122 reports and posters were identified as possibly satisfying the inclusion criteria. 33 studies, described in 40 publications, were excluded. Of these, ten were not randomised controlled trials, 21 were not of continuation
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ARTICLES
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% relapsed during trial
versus discontinuation design, one was a crossover study with no useable data, and in the remaining trial, participants had postpsychotic depression rather than a primary depressive disorder. 37 trials, described in 82 publications, satisfied the inclusion criteria (table).13–49 Data were not available from six of these trials.14,19,25,26,41,47 The quantitative analyses are therefore based on the results of 31 trials. In four of these trials21,22,30,35 where there were separately randomised strata, these were included separately in the analyses. Trials of most classes of antidepressant were identified, although most involved either a tricyclic antidepressant or a selective serotonin reuptake inhibitor (table). The trials included patients with a first episode and those recurrent disorders from various health-care settings (including both primary and secondary care). Seven trials17,24,30,34,35,37,43 (738 participants) provided information for 6 months’ follow-up; 1115,16,18,20,22,36,38,45,46,48,49 (2726 participants) at 12 months; three28,29,32 (240 participants) at 18 months; six13,27,33,39,40,44 (356 participants) at 24 months; and four21,23,31,42 (350 participants) at 36 months. Most therefore, were about trials of 12 months’ antidepressant therapy. Overall, results seemed similar for all classes of antidepressant (figure 1) and showed that continuing antidepressant therapy consistently reduced the risk of relapse (pooled odds ratio for relapse 0·30, 95% CI 0·22–0·38, 2p<0·00001; figure 2). The proportional risk reduction seemed to be similar in patients with shorter (1–2 months) and longer (4–6 months) treatment before randomisation and from 6 months to 36 months of randomised treatment (figure 2). There was statistically significant heterogeneity (234 52·0, p=0·02), between the trials, although inspection of the forest plots suggests that this heterogeneity is the result of quantitative rather than qualitative differences between trials. This odds ratio of 0·30 is roughly equivalent to a halving of the absolute risk of relapse: the average relapse rate on placebo was 41% compared with that on antidepressant of 19%. In the six trials of 2–3 years’ duration in which it was possible to obtain data about the number of patients relapsing in the first and subsequent years, the proportional risk reduction was similar in both periods (0–12 months, 81% reduction in odds: 12–36 months, 77% reduction in odds), although the absolute risk of relapse was twice as high in the first 12 months as it was in the subsequent 12–36 months (0–12 months control event rate 60%; 12–36 months event rate 29%; figure 3). There was no clear difference in either the treatment effect or the absolute risk of relapse in trials in which participants were randomised sooner (1–2 months) or later (4–6 months and ⭓12 months) after starting antidepressants (figures 2 and 4). For example, in trials with 1–2 months of prerandomisation treatment and 12 months’ follow-up, the average risk of relapse in the control group was 40%. In trials with 4–6 months of prerandomisation treatment and 12 months’ follow-up, the average risk of relapse in the control group was 35%. Findings were similar in trials with 2 years of randomised treatment (figure 4) More patients allocated to continue antidepressants than on placebo withdrew from the trials for reasons other than relapse or recurrence (active drug 18%, placebo 15%; OR 1·30, 95% CI 1·07–1·59; 2p=0·009). Only two trials reported data about suicide (five of 767 on maprotiline vs one of 374 controls,45 and one of 185 on sertraline vs none of 110 controls18). Even if all studies had reported data for this outcome, the numbers might not have been sufficient to yeild reliable results, since very
Allocated active antidepressant Allocated control
80 65 62
60 40
40
35
33 24
16
20
93 248 583 620
0 Duration of previous treatment
18 182 341 1014 986
1–2 months 4–6 months
Duration of +1 year treatment after randomisation
+1 year
43 84 132 130
81 209 338 339
1–2 months 4–6 months
+2 years
+2 years
Figure 4: Relapse rates after 1 or 2 years’ prolongation of antidepressant treatment in patients already treated for 1–2 or 4–6 months after an acute episode of depression
large-scale randomised evidence would probably be required to establish an effect on such an uncommon event.
Discussion On the basis of pooled results of 31 randomised trials that included 4410 patients, continuing treatment with antidepressants reduced the odds of depressive relapse by around two-thirds, which is approximately equivalent to a halving of the absolute risk. The treatment effect was similar across different classes of antidepressant. We are not aware of any previous methodologically satisfactory meta-analyses of these trials, although workers in a previous quantitative review of long-term antidepressant therapy reported a relative risk of relapse of 3·6 on drug discontinuation.50 Although the qualitative findings of the reviews are broadly equivalent, our review includes more trials and a formal meta-analysis that preserves the withinstudy randomised comparisons. The risk of relapse seemed similar across heterogeneous groups of patients including those who had recently responded to treatment of an acute episode of illness and those who had been successfully taking maintenance treatment for several months or even years. This finding is a clinically important simplification because current approaches to the treatment of depression try to distinguish between several stages in the recovery from depression and hypothesise different effects of treatment in each stage. In the current classification, response or partial remission refers to a clinically significant improvement; full remission occurs when symptoms have decreased to the extent that a reduction in intensity of treatment might be attempted; and recovery takes place when remission has lasted for a predefined period and discontinuation of treatment is being considered. This distinction between relapse and recurrence assumes that symptomatic improvement occurs before resolution of the underlying pathophysiology and that the risk of relapse decreases as the pathophysiology underlying the disorder resolves.12 Treatment is therefore divided into three stages: acute treatment phase, continuation therapy to prevent relapse,
659
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ARTICLES
and maintenance therapy to prevent recurrence. Within the trials included in the review, however, there does not seem to be a clear distinction between the continuation and maintenance phase treatment effects. Several factors might limit the general applicability of our results. The trials were mainly done in secondary care settings, with patients at a high risk of relapse. This is an important patient group contributing substantially to the prevalence and burden of disease posed by major depression. How our results would apply to patients who were under-represented in the trials is unclear, particularly those with milder illnesses who might have a low underlying risk of relapse. There was heterogeneity in the risk of relapse in these patients in these trials and yet, in proportional terms, the effect of treatment was roughly equivalent, suggesting that even though the absolute effect in low-risk patients might be small, there might still be a benefit. This issue needs further investigation in future randomised trials. The trials were heterogeneous in terms of diagnostic criteria, drugs used, and criteria for relapse (table), but the consistent effect of treatment across trials suggests that the proportional risk reduction does not depend on such factors. Unavoidably, the design of the trials included in this review necessitated that some patients were withdrawn from active treatment. Therefore, the possiblity is raised that the risk of relapse or recurrence might be increased by a direct quasi-pharmacological response to the withdrawal of medication per se rather than the relapse or recurrence being solely due to the underlying disorder. This problem has been identified for lithium, for which acute withdrawal leads to manic relapse.51,52 Trials with a withdrawal design quite clearly inflated the apparent efficacy of lithium.53 In this review, there did not seem to be an excess of cases within a month of drug discontinuation as is the case with lithium,54 but we cannot exclude the possibility that there is a related effect. If there is an effect, the effectiveness of continuation therapy could have been overestimated. We relied on published reports of aggregate data, which meant that we were unable to do a survival analysis making full use of the time-to-relapse of individual patients. A meta-analysis using individual patient data is currently underway to investigate whether the observed relative risk reduction is constant across all patient subgroups, and to provide estimates of the absolute risk of relapse at particular time points and for specific subgroups of patients.55 The evidence suggests that many patients with recurrent depressive disorders who have responded well to acute phase treatment would benefit from continued treatment with antidepressants. The absolute benefit for any particular patient will depend on his or her underlying risk of relapse. High withdrawal rates in patients on antidepressants means that the treatment effect for compliant patients who can tolerate long-term medication might be even greater than that recorded in trials. Although the total number of patients followed for 12 months was substantial, relatively few trials reported follow-up of longer than 12 months, and further long-term trials are needed in representative patients, including those at low risk. Few other interventions in psychiatry are supported by such robust findings based on more than 4000 patients in randomised trials. We cannot make specific recommendations about which patients should or should not be offered long-term treatment with antidepressants, because treatment will depend on an individual patient’s baseline risk, a patient’s treatment preferences, and the clinician’s prior beliefs. However, for patients who are still at appreciable risk of recurrence after 4–6 months of
660
treatment with antidepressants, another year (and probably more) of continuation treatment will approximately halve their risk. Contributors J Geddes initiated the review, contributed to data extraction, assessed the quality of studies, and did some of the analyses. He is the guarantor of the review. S Carney contributed to the design and writing of the protocol, managed the literature search, extracted data, and appraised study quality. C Davies extracted data, appraised study quality, and did some of the analyses. T Furukawa contributed to the design of the protocol, and appraised study quality. Guy Goodwin assessed study quality and contributed to the design and writing of the protocol. All authors helped to interpret findings and write the manuscript.
Conflict of interest statement None declared.
Acknowledgments We thank the Cochrane depression, anxiety, and neurosis group for their assistance with the literature search; Richard Peto and Jon Godwin of the Clinical Trial Service Unit for assistance with the analyses and preparation of the figures. Stuart Carney was funded by the Wellcome Trust during this study.
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