Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability

Journal of Affective Disorders 58 (2000) 19–36 www.elsevier.com / locate / jad

Research report

Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability Ian M. Anderson MRCP, MRCPsych, MD* Neuroscience and Psychiatry Unit, Room G809, Stopford Building, University of Manchester, Oxford Road, Manchester M13 9 PT, UK Received 7 December 1998; received in revised form 12 April 1999; accepted 25 May 1999

Abstract Background: A meta-analysis of the efficacy and tolerability of selective serotonin reuptake inhibitors (SSRIs) against tricyclic antidepressants (TCAs) in depressed patients was carried out. Methods: Efficacy data from 102 randomised controlled trials (10 706 patients) were pooled to provide a summary variance-weighted effect size. Tolerability data from 95 studies (10 553 patients) were combined to give variance-weighted relative risk of drop out for all reasons and for adverse effects from each study. The effect of age, treatment setting, severity and TCA dose were examined as well as the performance of individual SSRIs and TCAs where there were sufficient studies. Results: There is no overall difference in efficacy between SSRIs and TCAs (effect size 2 0.03, 95% confidence interval 2 0.09 to 0.03). TCAs do appear more effective in in-patients (20.23, 2 0.40 to 2 0.05) and amitriptyline is more effective than SSRI comparators (20.14, 2 0.25 to 2 0.03) but publication bias cannot be excluded. The SSRIs are better tolerated, with significantly lower rates of treatment discontinuations overall (relative risk 0.88, 0.83 to 0.93; number needed to treat 26) and due to side effects (0.73, 0.67 to 0.80; number needed to treat 33). Individual SSRIs show a similar advantage except for fluvoxamine which does not differ from the TCAs. Individual TCAs show a similar disadvantage in tolerability compared to SSRIs except for dothiepin against which SSRI treatment results in more side-effect related drop outs (2.64, 1.50 to 4.63; number needed to harm 12). Limitations: The evidence is from short-term studies and subgroup analyses may result in chance results. Conclusions: Overall efficacy between the two classes is comparable but SSRIs are not proven to be as effective as TCAs in in-patients and against amitriptyline. SSRIs have a modest advantage in terms of tolerability against most TCAs.  2000 Elsevier Science B.V. All rights reserved. Keywords: SSRIs; TCAs; Depression; Systematic review; Meta-analysis

1. Introduction

*Tel.: 1 44-161-2757-431; fax: 1 44-161-2757-429. E-mail address: [email protected] (I.M. Anderson)

The selective serotonin reuptake inhibitors (SSRIs) are increasingly becoming the agents of first choice in the treatment of depression, replacing the well

0165-0327 / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved. PII: S0165-0327( 99 )00092-0

20

I.M. Anderson / Journal of Affective Disorders 58 (2000) 19 – 36

established tricyclic antidepressants (TCAs) probably because of their better side-effect profile and safety. The number of prescriptions issued by general practitioners for the treatment of depression increased by 33% between 1993 and 1995 (Donoghue et al., 1996). The increase in prescription rates of TCAs was 12.4%, while prescriptions of SSRIs increased by 133.8% during that time. An analysis of the prescribing patterns of psychiatrists in the USA, working in out-patient private clinics, revealed that in 1993–1994, psychiatric patients were 2.3-times more likely to receive an antidepressant than in 1985 (Olfson et al., 1998). SSRIs accounted for approximately half of all prescriptions. SSRIs are more expensive than TCAs. The cost implications of the increasing use of SSRIs is large (Effective Health Care Bulletin, 1993) and has led to a heated debate over the cost-effectiveness of this change in prescribing pattern (Hotopf et al., 1996). There are now data from a large number of randomised controlled trials (RCTs) comparing SSRIs and TCAs and many meta-analyses have been carried out (e.g., Song et al., 1993, Anderson and Tomenson, 1994, 1995; Montgomery et al., 1994, Hotopf et al., 1997; Steffens et al., 1997). The available randomised controlled trials have serious limitations in helping to cast light on cost-effectiveness issues because they are nearly all short-term treatment studies, whereas guidelines indicate the need to continue treatment for many months (Paykel and Priest, 1992; Montgomery et al., 1993) and they are artificial compared to treatment that occurs in everyday practice. However, it is important to inform the debate with the best evidence on efficacy and tolerability available from RCTs in order to guide clinicians’ choice and, arguably, as one basis for cost-effectiveness analyses. In spite of the plethora of meta-analyses that have been published, few have examined clinically important questions related to subgroups of patients and drugs which may provide guidance in treating individual patients with specific antidepressants. In a previous meta-analysis comparing TCAs (and maprotiline) with SSRIs, we detected no difference in efficacy in the overall analysis. However, SSRIs appeared less effective than some individual TCAs, and in hospitalised patients (Anderson and Tomenson, 1994). In a second meta-analysis which addressed the issue of relative tolerability, we

found that fewer patients receiving SSRIs dropped out of treatment than those receiving TCAs, and that the main reason for discontinuation was attributed to side effects (Anderson and Tomenson, 1995), although the size of the effect was relatively small. This meta-analysis was carried out because of the importance of updating previous studies given the significant increase in the number of trials comparing SSRIs and TCAs since our previous studies; a larger data-set allows more confident estimates of effect and reduces the likelihood of chance findings. It also seems unlikely that many more RCTs of this nature will be carried out so we are probably close to having as much data as will be available. Our previous studies raised important questions with regard to certain types of patients and a possible greater efficacy of specific TCAs. The larger number of studies allows further exploratory analysis of subgroups of trials in order to address these clinically important questions.

2. Methods

2.1. Selection of studies Randomised controlled trials investigating the efficacy of SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline, or citalopram) against a TCA in patients with unipolar major depressive illness were identified from previous meta-analyses and reviews, by manual cross-referencing and a MEDLINE search up to May 1997 (search terms: drug name; randomised controlled trial; controlled trial; depression and variants) with no language restrictions. The TCAs investigated included clomipramine, amitriptyline, imipramine, dothiepin, desipramine, doxepin, nortriptyline, nomifensine and lofepramine. The tetracyclic antidepressant maprotiline was also included in the analysis as it has the same mechanism of action as the TCAs. Studies comparing SSRIs with older ‘‘atypical antidepressants’’ (i.e., those that do not inhibit monoamine reuptake) were not included in the analyses because they have varying different mechanisms of action, make up only a small proportion of prescriptions and there is uncertainty as to whether they are as effective as TCAs (Moller and Haug,

I.M. Anderson / Journal of Affective Disorders 58 (2000) 19 – 36

1988; Kasper et al., 1992). Newer antidepressants (nefazodone, venlafaxine and mirtazapine) were not included as they have heterogeneous pharmacology and remain relatively infrequently used. The principal aim of the study was comparison of the new ‘‘standard’’ treatment, the SSRIs with the established TCAs. Studies using mean doses of less than 100 mg of a TCA were excluded from an earlier meta-analysis (Anderson and Tomenson, 1994); however, in the present paper, 22 studies with low-dose TCAs were included and a sensitivity analysis performed. I was careful to avoid duplication of studies, especially relevant for multi-centre studies where individual studies were often reported separately; in these cases only the combined multi-centre report was used. Following the application of these exclusion criteria, 102 studies, 16 of which were placebo controlled, involving 10 706 patients randomised to active treatment, were entered into the overall analysis of efficacy (Table 1) with slightly fewer studies available for analysis of tolerability (see below). Eighty-two of the studies used DSM-III, DSM-IIIR, Feighner (Feighner et al., 1972) or Research Diagnostic Criteria (Spitzer et al., 1975) for major depression (Table 1). The median duration of active treatment was six weeks with 55 studies lasting this time. Twenty eight studies lasted four or five weeks and 20 studies more than six weeks but only one lasted more than 12 weeks (Fontaine, 1991 which lasted for 24 weeks). The median number of patients assessed in these trials was 60 (range 14 to 953).

2.2. Assessment of efficacy The 17- or 21-item Hamilton Rating Scale for Depression (HAMD) was the most commonly used measure of efficacy in the selected clinical trials, while the Montgomery and Asberg Depression Rating Scale (MADRS) was used in nine studies. Relative efficacy was assessed as an effect size based on the relative reduction in rating scale scores over the duration of the trial, as discussed under Statistical analysis below. A fuller discussion of the relative merits of the various methods of assessing treatment outcome can be found in an earlier paper (Anderson and Tomenson, 1994). Where possible I used values that included the maximum number of

21

patients (i.e., intention to treat or last observation carried forward rather than completer analysis).

2.3. Subgroup analysis The efficacy of the TCAs and SSRIs in treating depression was addressed in the following subgroups of patients (Table 1): adult (age , 65 in most studies but up to 70 years in a few) and elderly ( . 65 years) patients; in-patients and out-patients and those in general practice; less and more severely ill patients based on lower or higher initial HAMD scores determined by a median split of the initial HAMD, carried out separately for studies using the 17- and 21-item HAMD (respective medians 24.45 and 26.04). Twenty-three studies were excluded because one or other treatment arms of initial HAMD scores straddled the median value. A separate analysis of the in-patient subgroup has been published elsewhere (Anderson, 1998a). As there is interest in how individual antidepressants perform (indeed, patients can only be prescribed a single drug rather than a group), analyses of individual SSRI and individual TCA were carried out against the comparator group where there were a minimum of five studies reporting efficacy or overall discontinuation rates. Comparison with individual drugs was not possible because of the large number of potential individual comparisons and because the number of studies for each comparison was small. It is generally believed that TCA dose is important but there are difficulties in analysis because of the lack of evidence about minimum effective doses of individual drugs and inadequacies in reporting in studies. The studies also differed as to whether they used fixed or flexible doses. To attempt to address this issue I analysed separately studies using TCA doses generally accepted to be therapeutic (‘‘high dose’’, . 149 mg) and those using lower doses which are widely considered sub-therapeutic ( , 100 mg) (Montgomery et al., 1993) where doubt about clinical effectiveness has been raised (Blashki et al., 1971; Thompson and Thompson, 1989).

2.4. Treatment discontinuation The data set available for analysis of treatment discontinuation differed to some degree from that for

I.M. Anderson / Journal of Affective Disorders 58 (2000) 19 – 36

22

Table 1 Details of all studies included in the meta-analysis Study

Diagnosis

TCA

Fluvoxamine Amin et al., 1984 Amore et al., 1989 Bramanti et al., 1988 Claghorn et al., 1996 de Jonghe et al., 1991a a De Wilde and Doogan, 1982 De Wilde et al., 1983 Dick and Ferrero, 1983 Dominguez et al., 1985 a Fabre et al., 1996 Feighner et al., 1989b a Gasperini et al., 1992 Gonella et al., 1990 Guelfi et al., 1983 Guy et al., 1994 Harris et al., 1991 Itil et al., 1983 a Kasper et al., 1990 Klok et al., 1981 Lapierre et al., 1987 a Lydiard et al., 1989 March et al., 1990 Mullin et al., 1988 Nathan et al., 1990 Norton et al., 1984 a Ottevanger, 1995 Rahman et al., 1991 Remick et al., 1994 Roth et al., 1990

DSM-III DSM-III DSM-III DSM-IIIR DSM-III RDC RDC RDC DSM-III DSM-IIIR DSM-III DSM-IIIR DSM-III CLINICAL RDC DSM-III RDC DSM-III VITAL DSM-III DSM-III DSM-III DSM-III DSM-III DSM-III RDC DSM-III DSM-III DSM-III

Imipramine Imipramine Imipramine Imipramine Maprotiline Clomipramine Clomipramine Clomipramine Imipramine Imipramine Imipramine Amitriptyline Imipramine Imipramine Imipramine Amitriptyline Imipramine Maprotiline Clomipramine Imipramine Imipramine Imipramine Dothiepin Desipramine Imipramine Clomipramine Dothiepin Amitriptyline Desipramine

Fluoxetine Altamura et al., 1989 Beasley et al., 1993 Bowden et al., 1993 Bremner, 1984 Bressa et al., 1989 Chouinard, 1985 b Cohn and Wilcox, 1985 Corne and Hall, 1989 de Jonghe et al., 1991 b Dowling et al., 1990 Fabre et al., 1991 Fairweather et al., 1993 Fawcett et al., 1989 Feighner and Cohn, 1985 Feighner, 1985 b Feighner et al., 1989a b Ginestet et al., 1989 Judd et al., 1993 Keegan et al., 1991 Kerkhofs et al., 1990 Kuha et al., 1991 Laakmann et al., 1988 Levine et al., 1987 Loeb et al., 1989 Manna et al., 1989 Masco and Sheetz, 1985 b Nielson et al., 1993 Noguera et al., 1991 Pakesch and Dossenbach, 1991 Peters et al., 1990 Poelinger and Haber, 1989 Remick et al., 1989 Remick et al., 1993 Robertson et al., 1994

DSM-III RDC DSM-IIIR RDC DSM-III RDC DSM-III RDC DSM-III DSM-III DSM-IIIR CLINICAL DSM-III DSM-III RDC DSM-III DSM-III DSM-IIIR DSM-III RDC RDC ICD9 RDC DSM-III DSM-III RDC DSM-III DSM-III Kielholz/Poeldine ICD9 Kielholz/Poeldine DSM-III DSM-III DSM-IIIR

Amitriptyline Amitriptyline Desipramine Imipramine Imipramine Amitriptyline Imipramine Dothiepin Maprotiline Dothiepin Nortriptyline Amitriptyline Amitriptyline Doxepin Amitriptyline Imipramine Clomipramine Amitriptyline Amitriptyline Amitriptyline Maprotiline Amitriptyline Imipramine Imipramine Clomipramine Amitriptyline Imipramine Clomipramine Clomipramine Amitriptyline Maprotiline Doxepin Desipramine Lofepramine

Subgroup analysis c

P

H

C P C P

H

C P P P

H H H

C C C C C

L P

P P P C P

H H H H

H H

C H C C

P

C C

H

L H H H

C

P C C C

H H L H L L H

C

H C C C C

C

P H H H H L

H L H

C L C C C C

L H H

O1I IP UK OP OP IP OP IP OP OP IP IP OP IP IP OP OP IP IP IP OP OP OP IP OP IP UK OP OP

IP OP O1I OP OP OP OP GP OP OP OP UK OP OP OP OP IP OP OP O1I O1I OP UK OP IP OP OP OP OP OP OP O1I OP O1I

M S M M S M S S

S S M

M S S M S S S

E

S

E S M

M S M M M M M S M S

M S S M S M S S M M M

E E

SSRI (N)

TCA (N)

Efficacy effect size

161 15 28 44 21 15 21 16 35 46 21 30 10 59 17 24 22 21 13 22 17 13 26 17 35 20 24 13 27

153 10 29 44 21 15 23 13 35 48 27 26 10 68 19 26 25 20 13 21 18 15 24 18 31 20 24 9 24

0.07 2 0.43 0.16 2 0.04 2 0.14 0.44 2 0.29 0.03

11 65 28 16 15 25 54 28 34 30 72 30 19 78 22 52 26 30 18 9 21 52 22 15 15 20 21 60 91 40 73 38 24 93

11 71 30 20 15 28 54 34 44 30 84 30 19 79 22 45 24 28 19 10 18 53 28 15 15 21 22 60 48 41 75 37 15 90

2 0.53 0.13 2 0.04 0.98

0.01 0.43 0.19 0.08 2 0.07 2 0.76 2 0.52 2 0.23 2 0.78 2 0.07 0.04 0.11 2 0.05 0.17 0.41 0.00

0.62 2 0.23 2 0.24 2 0.36 2 0.06 0.08 0.26 2 0.05 2 0.22 2 0.34 0.44 2 0.49 0.26 2 0.21 0.00 2 0.70 0.70 0.66 0.18 0.23 0.14 2 0.13 0.13 2 0.33 2 0.71 2 0.09

Relative risk total drop outs

Relative risk side effect drop outs

Relative risk failure drop outs

0.09 2.00 1.04 0.67 1.00 1.09 1.18 1.19 1.12

0.20 0.33 0.92 1.00 1.00 1.09 0.89 1.25 0.81 0.61 0.87

1.00 5.00 1.33 0.33 1.00 1.09 0.88 3.00 3.12

0.42

0.15

0.81 1.46 1.00 2.00 0.95 0.50 1.33 1.46 0.23 4.44 2.00 1.00 0.53

0.19 0.38 1.00 3.00 0.32 3.00 0.49 1.17 2.66 0.55 1.00 0.21

0.67 1.33 2.00 0.75 0.56 2.08

0.54 0.20 1.00 0.12 0.33 3.64

1.61 1.00 1.00 3.35 0.11 1.04

1.88 0.86

6.00 0.58

2.50 0.40

0.73 0.78 0.38 1.05

0.40 0.74 0.33 0.69

5.00 1.52 0.33 1.77

1.31 0.73

2.80 3.29

0.93 0.16

0.69

1.00

0.92

4.00

5.00

2.00

0.21 1.03 0.81

0.23 1.03 0.33

1.05 1.03 6.67

1.27 0.27 0.73

1.10 0.10 0.17

1.95 0.40

1.73 3.00 1.11 1.17 1.14 0.33 1.67 0.56 1.67 0.89 0.23 3.54 1.67 1.29 0.40 0.67

0.58

I.M. Anderson / Journal of Affective Disorders 58 (2000) 19 – 36

23

Table 1. Continued Study

Diagnosis

TCA

Subgroup analysis c

Ropert, 1989 South Wales ADTG, 1988 Stark and Hardison, 1985 Tamminen and Lehtinen, 1989 Taneri and Kohler, 1989 Tollefson et al., 1994 Upward et al., 1988 Young et al., 1987

DSM-III DSM-III DSM-III RDC ICD9 DSM-IIIR CLINICAL RDC

Clomipramine Dothiepin Imipramine Doxepin Nomifensine Imipramine Amitriptyline Amitriptyline

C C C

Paroxetine Arminen et al., 1992 Bascara, 1989 Battegay et al., 1985 Bignamini and Rapisarda, 1992 Bourin, 1990 Byrne, 1989 Christiansen et al., 1996 DUAG, 1990 Dunbar et al., 1991 Dunner et al., 1992 Gagiano et al., 1989 Geretsegger et al., 1995 Guilibert et al., 1989 Hutchinson et al., 1991 Kuhs and Rudolf, 1989 Laursen et al., 1985 Moller et al., 1993 Moon and Vince, 1996 Nielsen et al., 1991 Øhrberg et al., 1992 ´ Pelicier and Schaeffer, 1993 Ravindran et al., 1997 Shillingford et al., 1990 Staner et al., 1995 Stott et al., 1993 Stuppaeck et al., 1994

DSM-IIIR DSM-III CLINICAL DSM-III UK CLINICAL CLINICAL DSM-III DSM-III DSM-III DSM-III DSM-III DSM-III DSM-III DSM-III ICD8 DSM-III DSM-IIIR DSM-III DSM-IIIR RDC CLINICAL DSM-III RDC CLINICAL DSM-III

Imipramine Amitriptyline Amitriptyline Amitriptyline Clomipramine Amitriptyline Amitriptyline Clomipramine Imipramine Doxepin Amitriptyline Amitriptyline Clomipramine Amitriptyline Amitriptyline Amitriptyline Amitriptyline Desipramine Imipramine Imipramine Clomipramine Clomipramine Dothiepin Amitriptyline Amitriptyline Amitriptyline

DSM-IIIR DSM-III DSM-IIIR DSM-IIIR DSM-IIIR DSM-IIIR

Amitriptyline Amitriptyline Dothiepin Imipramine Clomipramine Amitriptyline

DSM-III DSM-IIIR DSM-IIIR DSM-III DSM-IIIR

Nortriptyline Clomipramine Desipramine Amitriptyline Dothiepin

CLINICAL CLINICAL CLINICAL CLINICAL DSM-III DSM-III

Maprotiline Clomipramine Amitriptyline Imipramine Amitriptyline Maprotiline

Sertraline Bersani et al., 1994 Cohn et al., 1990 Doogan and Langdon, 1994 Fontaine, 1991 Lepine and Wiseman, 1996 Lydiard and The Depression Research Group, 1996 McEntee et al., 1996 Moon et al., 1994 Ravindran et al., 1995 Reimherr et al., 1990 Thompson, 1991 Citalopram Bouchard et al., 1987 DUAG, 1986 Gravem et al., 1987 Rosenberg et al., 1994 Shaw, 1986 Timmerman et al., 1987 a

P

C C

L H H L H H H

L L L H H C H P L L

C C C

H H H H

C

C

L H H L H

C C

L L

C

P C

H L P

L C C

P P P

C H H C C

OP UK OP O1I OP OP OP OP

IP UK OP OP OP IP GP IP OP OP OP IP UK GP UK IP IP GP IP OP OP GP OP IP GP IP

M S S M M

S S S M M S E S S M M M S M

E E E EA

M E

S M S

S

SSRI (N)

TCA (N)

Efficacy effect size

Relative risk total drop outs

Relative risk side effect drop outs

Relative risk failure drop outs

55 22 182 21 15 62 11 32

48 24 184 21 13 60 12 32

0.28 0.21 2 0.12 0.03 0.15 0.12

0.68 1.94 1.01 1.11

0.34 15.38 0.64 2.65

1.13 1.17

0.38 1.87 1.00

0.22 0.94 5.00

1.00 2.81 1.00

21 20 8 151 38 23 62 56 207 96 30 28 40 46 14 16 81 60 13 65 41 479 42 21 243 68

29 23 6 152 37 26 63 46 204 92 34 31 39 21 17 14 74 62 15 65 42 474 43 19 262 66

0.21 0.02 2 1.24 2 0.09 2 0.33 2 1.12 2 0.26 2 1.11 0.04 0.25

1.11 0.57 0.34 1.52 1.59 1.33 0.96 0.59 0.80 1.15 0.96 0.89 0.73 0.60 2.00 0.61 0.76 1.16 0.73 0.69 1.23 0.73 0.83 1.13 0.70 1.07

1.10 0.57 0.30 1.57 1.02 0.33 1.29 0.09 0.65 1.26 1.02 1.37 0.59 0.74 5.00 0.55 0.61 1.29 0.31 0.72 1.02 0.67 1.57 0.90 0.68 0.87

1.28

31 157 83 43 81 130

30 77 96 45 83 129

0.16 2 0.27 0.26 0.50 0.10 2 0.21

0.75 0.96 1.12 1.13 0.69

0.34 0.87 2.79 1.39 0.78 0.25

0.01 0.02 0.18 2 0.04 2 0.55 2 0.23 2 0.01 2 0.75 0.17 0.19 0.09 0.08 2 0.68 0.06 0.02

OP OP GP OP OP OP

M M S M

OP OP OP OP GP

M M M S

105 47 34 126 79

105 48 30 122 80

0.11 0.17 2 0.16 2 0.25 0.32

0.43 0.82 0.97 0.73

O1I IP O1I GP O1I IP

S M S M S S

39 50 12 328 24 14

34 52 12 85 20 13

0.13 2 0.47 2 0.98 2 0.03 2 0.02 2 0.29

1.50 0.89 0.73 0.41 0.21

E

E

0.62 0.22 0.51 0.93

0.11 0.89 0.46 0.17 1.07

0.91 1.10 1.54 1.67 1.29 1.20 1.47 0.66 2.67 1.30 0.19 1.00 0.36 1.12 3.10 0.56 1.01 1.02 1.17 0.52 1.81 0.24 1.26

0.21 0.78 0.77 1.04

1.08 1.83

2.48 0.89 1.22 0.67

One of the studies included in Amin et al., 1984. One of the studies included in Beasley et al., 1993. c Definitions: C 5 complete data; P 5 placebo controlled; H 5 TCA dose . 149 mg; L 5 TCA dose # 100 mg; GP 5 general practice study; OP 5 out-patient study; IP 5 in-patient study; O 1 I 5 out- 1 in-patient study; S 5 greater severity; M 5 milder severity; E 5 elderly; EA 5 elderly 1 younger adults. b

24

I.M. Anderson / Journal of Affective Disorders 58 (2000) 19 – 36

the efficacy analysis with some studies providing data for one analysis but not the other. There were also minor differences in the data sets for the different discontinuation analyses, e.g., not all studies provided data on discontinuations due to treatment failures. Ninety-five studies were included in the analysis of overall treatment discontinuation, 95 studies for discontinuation due to side effects and 82 studies for discontinuation due to treatment failure. Nineteen studies providing efficacy data did not provide information on the overall number of drop outs, while an additional 12 studies provided overall drop out data that were not analysed for efficacy. One contributory factor was the need to use individual studies from multicentre trials for one analysis but the combined report for another. The relative tolerability of SSRIs and TCAs was assessed by calculating the relative risk of treatment discontinuation (see Statistical analysis) for all reasons (total drop outs) and for those due to adverse effects (side effect drop outs). Drop outs due to treatment failure were also analysed.

2.5. Statistical analysis All analyses were carried out using Arcus Quickstat Biomedical (Research Solutions, Cambridge, UK).

2.5.1. Efficacy analysis Efficacy analyses were conducted according to the methods of Hedges and Olkin (1985). For each study, a standardised effect size and its 95% confidence interval (95% CI) were calculated for the difference between SSRI and TCA from the mean reduction in rating scale scores (initial minus final score). For studies where the standard deviations of scores were not supplied (53 studies) effect sizes were calculated using an estimated variance by using the pooled variance from the studies with complete data involving the same rating scale. Statistical heterogeneity of the results from individual studies was examined using Cochran’s Q test (Hedges and Olkin, 1985). A summary varianceweighted effect size was then calculated which gives more weight to larger studies where the effect size was estimated more precisely. For homogeneous data

a fixed-effects model was used (where it is assumed that a common underlying effect is being pooled); where there was significant heterogeneity ( p , 0.05) a random-effects model was applied, as no common population effect could be assumed (DerSimonian and Laird, 1986). I indicate where random-effects models have been applied in the relevant figures. Results are expressed as an effect size and 95% CI with a significance level, if appropriate. A positive effect size indicates an advantage to the SSRI and a negative effect size an advantage to the TCA.

2.5.2. Discontinuation analysis The ratio of the risks of patients stopping treatment with SSRIs compared with those discontinuing TCA treatment was calculated for each treatment group for total drop outs and for discontinuations due to side effects and treatment failures. The relative risk of discontinuation was calculated as: ratio of SSRI drop outs / SSRI total number divided by TCA drop outs / TCA total number. The complement of the risk ratio (1 2 risk ratio) gives the relative risk reduction comparing one treatment with another. For the main significant findings the absolute difference in risk expressed as a percentage (SSRI drop outs / SSRI total number minus TCA drop outs / TCA total number) and its reciprocal (the number needed to treat, NNT; or number needed to harm, NNH if the comparator has an advantage) were also calculated to aid interpretation. Variance-weighted pooling of data from individual studies was done in a similar way as for the efficacy data. A relative risk of less than one indicates an advantage to SSRIs. 2.5.3. Sensitivity analysis and publication bias Sensitivity analysis was performed by analysing separately the larger studies ( . 100 patients), those which were placebo controlled and, for efficacy, those with complete data. The extent of publication bias was examined by means of funnel plots in which sample size was plotted against the effect size or the natural logarithm of the risk ratio for individual studies (Egger et al., 1997). These graphs are based on the principle that precision in estimating the underlying treatment effect increases with the sample size of the component studies. Results from small studies tend to

I.M. Anderson / Journal of Affective Disorders 58 (2000) 19 – 36

scatter widely at the base of the plot, while those from larger studies, which are less likely to be subject to publication bias, are less dispersed at the top. In the absence of bias, the plot resembles a symmetrical inverted funnel. Asymmetry is suggestive of publication bias.

3. Results

3.1. Efficacy 3.1.1. All SSRIs versus TCAs A total of 10 706 patients from 102 studies were included in the efficacy analyses, of whom 5533 received an SSRI and 5173 a TCA. The results are displayed in Fig. 1. There were no significant differences in efficacy between the SSRIs and the TCAs in the total patient population or in the subgroups which considered older and younger patient populations, high- and low-severity groups, and high- and low-dose TCA groups. In addition, no significant difference in efficacy between the drug

25

classes was observed in the subgroups containing general practice and out-patients; however, the inpatient group showed an advantage to the TCAs ( p 5 0.012). In the sensitivity analysis, there was no statistical difference in efficacy observed between the SSRIs and the TCAs in studies with complete data, those that were placebo controlled or larger studies ( . 100 patients), although the latter showed a smaller effect size in favour of TCAs. The results are illustrated in Fig. 1. The funnel plots constructed for all studies and for in-patient studies were symmetrical (data not shown) providing no evidence for publication bias.

3.1.2. Individual SSRIs The efficacy of the five individual SSRIs compared with a TCA comparator are presented in Fig. 3 for all studies. There were no significant differences in efficacy between any of the individual SSRIs and the TCAs although the results with paroxetine and citalopram showed a non-significant trend in favour of the comparator TCAs.

Fig. 1. Plot showing the relative effect size of overall and subgroup analyses of studies comparing SSRIs and TCAs.

26

I.M. Anderson / Journal of Affective Disorders 58 (2000) 19 – 36

asymmetrical, indicating that publication bias could not be ruled out (Fig. 2).

3.2. Treatment discontinuation

Fig. 2. Funnel plot to investigate publication bias in efficacy analyses of amitriptyline vs. SSRIs.

3.1.3. Individual TCAs The efficacy of six individual TCAs compared with an SSRI comparator was investigated. In the analysis of all studies, there was no difference in efficacy between the individual TCA and their SSRI comparator (Fig. 4), with the exception of amitriptyline which was found to be more effective ( p 5 0.012). The funnel plot for amitriptyline studies was

3.2.1. All SSRIs versus TCAs There were 10 553 patients from 95 studies included in the analysis of treatment discontinuation (Table 2). In the total patient population, more patients taking TCAs discontinued treatment than did those receiving SSRIs (31.4% vs. 27.0%, p , 0.01). This pattern was the same across study setting and was evident in general practice patients ( p , 0.01), although it did not reach significance in in-patients. Similarly, more patients receiving TCAs discontinued treatment than did those receiving SSRIs in the subgroup of studies dealing with the adult patients ( , 65 / 70 years; p , 0.01), and in both the high ( p , 0.05) and lower dose ( p , 0.0001) TCA studies. There were more antidepressant treatment discontinuations generally in elderly patients ( . 65 years) than adults (36.5% vs. 29.2%). Although there was a slightly lower drop out rate on SSRIs compared with TCAs in the elderly (10 studies) this was

Fig. 3. Plot showing the relative effect size of the individual SSRIs against TCA comparators.

I.M. Anderson / Journal of Affective Disorders 58 (2000) 19 – 36

27

Fig. 4. Plot showing the relative effect size of individual TCAs against SSRI comparators. The small number of studies involving nortriptyline, lofepramine and doxepin prevented them from being included in the individual TCA analysis.

Table 2 Treatment discontinuation in studies comparing SSRIs and TCAs Overall drop outs

All studies Placebo controlled . 100 patients High dose Low dose GP patients Out-patients In-patients Adult Elderly

Side-effect drop outs

Failure drop outs

Na

Relative risk

95% CI b

Na

Relative risk

95% CI b

Na

Relative risk

95% CI b

95 16 32 39 18 9 50 22 85 10

0.88 0.92 0.86 c 0.90 c 0.81 0.78 0.90 0.88 0.89 c 0.91

0.83–0.93 0.84–1.01 0.79–0.94 0.78–1.04 0.73–0.91 0.68–0.90 0.84–0.97 0.75–1.03 0.82–0.97 0.78–1.06

95 17 33 40 17 8 52 21 85 9

0.73 0.70 0.68 c 0.65 0.72 0.75 0.72 0.66 0.70 0.91

0.67–0.80 0.60–0.82 0.58–0.80 0.55–0.78 0.61–0.85 0.61–0.85 0.64–0.80 0.50–0.87 0.63–0.77 0.74–1.11

82 14 28 35 13 7 45 19 73 8

1.10 1.26 1.15 1.15 0.85 0.98 1.09 1.13 1.11 1.02

0.95–1.28 0.99–1.61 0.96–1.37 0.93–1.42 0.60–1.20 0.64–1.50 0.89–1.35 0.84–1.51 0.95–1.30 0.62–1.68

a

N 5 Number of studies. 95% CI 5 95% confidence interval. c Random effects. b

not significant. The risk difference for total drop outs including all studies was 2 3.9% (25.6 to 2 2.2%, p , 0.0001), which gives an NNT of 26 (18 to 46); in other words, 26 patients would need to be treated with an SSRI rather than a TCA to prevent one drop out with a 95% confidence interval of 18 patients to 46 patients. The number of dropouts in longer studies ( . six weeks) was greater than in shorter

studies (four to six weeks) (31.5% vs. 28.3%) and the respective NNTs were 17 (8 to 105) and 45 (23 to 5264). Ninety-five studies (10 839 patients) provided data for discontinuation due to side effects with more patients receiving TCAs than SSRIs discontinuing treatment for this reason (17.3% vs. 12.4%, p , 0.0001). The increased risk of patients receiving

I.M. Anderson / Journal of Affective Disorders 58 (2000) 19 – 36

28

TCAs discontinuing due to side effects was noted in both the low ( p , 0.0001) and high dose TCA group ( p , 0.0001) and the adult patient group ( p , 0.01). The discontinuation rate due to side effects was higher in elderly patients than younger adults (21.8% vs. 14.7%) but there was minimal advantage to SSRI treatment over TCAs in this elderly sub-group (21.3% vs. 22.4%). The risk difference for sideeffect related drop outs including all studies was 2 3.1% (24.7% to 2 1.5%, p , 0.001) which gives an NNT of 33 (22 to 67). The number of dropouts due to side effects in longer studies ( . six weeks) was greater than in shorter studies (four to six weeks) (15.8% vs. 14.2%) and the respective NNTs were 18 (11 to 42) and 40 (24 to 157). Eighty-two studies with 9406 patients provided data for the analysis of discontinuation due to treatment failure. Slightly more patients on SSRIs stopped treatment for this reason but this did not reach significance (6.3% vs. 6.0%). Sensitivity analysis revealed comparable results when studies that were placebo controlled or contained more than 100 patients were considered separately (Table 2). Funnel plots for the analyses of overall drop outs and drop outs due to side effects did not suggest that publication bias accounted for the advantage of the SSRIs (data not shown).

3.2.2. Individual SSRIs In the analysis of individual SSRIs, significantly fewer patients receiving paroxetine discontinued treatment than the TCA comparator ( p , 0.001). While not statistically significant, the values of the

relative risks found with the other SSRIs were similar to that of paroxetine, with the exception of fluvoxamine which was not different to the TCAs (Table 3). When the discontinuations due to side effects were considered separately, significantly fewer patients receiving fluoxetine ( p , 0.01), paroxetine ( p 5 0.001), sertraline ( p , 0.05) and citalopram ( p , 0.01) discontinued for this reason than did patients receiving the TCA comparator (Table 3). As with total drop outs, fluvoxamine did not differ significantly from TCAs.

3.2.3. Individual TCAs There were more treatment discontinuations with amitriptyline ( p , 0.01) and clomipramine ( p , 0.01) than with the SSRI comparator. Although nonsignificant, the size of the relative risks with imipramine and desipramine were comparable (Table 4). The only TCA that showed fewer overall drop outs than SSRIs was dothiepin, although this did not reach significance. When discontinuations due to side effects were considered, significantly more patients receiving amitriptyline ( p , 0.001), imipramine ( p , 0.0001), and clomipramine ( p , 0.001) discontinued for this reason than did patients on the comparator SSRI, with similar, although non-significant, results for desipramine. In contrast, more SSRI-treated patients discontinued due to side effects than with dothiepin ( p , 0.001; Table 4). The risk difference was 8.9% (1.9 to 16.8%; NNH 5 12).

Table 3 Treatment discontinuation in studies comparing individual SSRIs and TCAs Overall drop outs

Fluvoxamine Fluoxetine Paroxetine Sertraline Citalopram a

Failure drop outs

Relative risk

95% CI b

Na

Relative risk

95% CI b

Na

Relative risk

95% CI b

25 30 26 9 5

1.10 0.87 c 0.85 0.91 0.73

0.86–1.19 0.74–1.03 0.77–0.93 0.79–1.06 0.53–1.02

24 29 26 10 4

0.94 0.63 c 0.77 0.74 0.43

0.72–1.22 0.48–0.84 0.67–0.88 0.59–0.93 0.24–0.79

22 26 24 6 4

0.85 1.18 1.12 0.98 1.31

0.53–1.36 0.89–1.57 0.91–1.39 0.58–1.67 0.62–2.74

N 5 Number of studies. 95% CI 5 95% confidence interval. c Random effects. b

Side-effect drop outs

Na

I.M. Anderson / Journal of Affective Disorders 58 (2000) 19 – 36

29

Table 4 Treatment discontinuation in studies comparing SSRIs and individual TCAs Overall drop outs

Amitriptyline Imipramine Clomipramine Dothiepin Desipramine

Side-effect drop outs

Failure drop outs

Na

Relative risk

95% CI b

Na

Relative risk

95% CI b

Na

Relative risk

95% CI b

31 25 17 8 6

0.86 0.92 c 0.82 1.24 0.72

0.77–0.95 0.80–1.05 0.70–0.95 0.95–1.62 0.50–1.04

31 26 14 7 4

0.75 0.66 0.63 2.64 0.56

0.64–0.88 0.57–0.77 0.50–0.80 1.50–4.63 0.29–1.07

27 24 14 6 4

0.99 1.16 1.33 0.98 1.40

0.77–1.28 0.90–1.49 0.92–1.91 0.50–1.91 0.47–4.22

a

N 5 Number of studies. 95% CI 5 95% confidence interval. c Random effects. b

4. Discussion The efficacy of the SSRIs as a group does not differ significantly from that of the TCAs as a group. This finding is consistent with previous meta-analyses (Anderson and Tomenson, 1994; Song et al., 1993) and studies investigating individual SSRIs (Ottevanger, 1991; Pande and Sayler, 1993). However, the TCAs demonstrated greater efficacy in hospitalised patients, although this benefit of TCAs was not observed in patients with more severe forms of depression as measured by an initial high HAMD score. I have previously presented the results in hospitalised patients and discussed explanations for these results (Anderson, 1998a). If this represents a true finding, the reason for the TCA advantage may not be related simply to severity of depression. Inpatients include those hospitalised for a variety of reasons, some of which may not directly relate to degree of depression. Furthermore, in-patients more often present with melancholia and are at a greater risk of suicide (Stage et al., 1998). However, the efficacy of SSRIs in treating such patients has been reported (Nielsen et al., 1991; Tignol et al., 1992; Heiligenstein et al., 1993), making conclusions difficult to draw and the answer may be due to a factor unrelated to patient status such as the pharmacology of the TCAs involved (see also Anderson, 1998a). Clomipramine and amitriptyline inhibit both noradrenaline and serotonin reuptake and the superior efficacy observed in hospitalised patients appears to be due to studies involving these TCAs. However, caution is required in the interpretation of this result

as there exists no statistically significant difference in efficacy between dual action and noradrenergic TCAs, and because the grouping of TCAs is not clear cut (see below). No significant difference in efficacy compared with the TCAs was noted for any of the individual SSRIs although there were trends for paroxetine ( p 5 0.07) and citalopram ( p 5 0.097). This may be due to the particular TCA comparator. Paroxetine and citalopram were compared with amitriptyline in 52% and 33% of studies, respectively. Results of the analysis show amitriptyline to be the only TCA with significantly greater efficacy than the SSRI comparator. However, as publication bias amongst amitriptyline studies cannot be ruled out, this result must not be over-interpreted. In addition, it is difficult to translate statistical significance into clinical importance. An effect size is a standardised value and interpreting what it might mean in practice is not straightforward. A value of 0.14 is generally regarded as small; however, we found that the effect size of antidepressants against placebo is about 0.4 (Anderson and Tomenson, 1994). The advantage of amitriptyline over SSRIs is therefore about a third of that of an antidepressant over placebo, which would translate into roughly a 10% difference in response rate. If true, the efficacy of amitriptyline may be related to dual serotonin and noradrenaline reuptake inhibition; however, the lack of advantage to imipramine and particularly to clomipramine argues against this. This is of importance because the Danish University Antidepressant Group (DUAG) studies (DUAG,

30

I.M. Anderson / Journal of Affective Disorders 58 (2000) 19 – 36

1986, 1990) are frequently used to support arguments for TCAs having an efficacy advantage over SSRIs. Selective quoting of studies is dangerous and an overall advantage to clomipramine has not been shown in this systematic analysis. A pharmacological property that amitriptyline does possess more than other TCAs is 5-HT 2A receptor antagonism (Cusack et al., 1994) and it is possible that dual uptake inhibition, together with serotonin receptor blockade, may confer an advantage which may be worth exploring further. The SSRIs have a significantly lower rate of overall treatment discontinuation than do the TCAs. While this was only significant for paroxetine in the individual analysis the relative risks for fluoxetine, sertraline and citalopram were comparable. The difference in overall discontinuation rate appears to be entirely accounted for by fewer SSRI patients stopping treatment due to side effects, suggesting that SSRIs are better tolerated. While this is a relatively small advantage to SSRIs and arguably of uncertain clinical significance, it does appear that the risk difference is larger in studies of longer duration (and hence the NNT is smaller) which may have important clinical implications when treatment periods of more than six months are advocated (Paykel and Priest, 1982; Montgomery et al., 1993). Although drop outs due to side effects may be a crude way to assess tolerability, they can provide a useful measure of acceptability (Lader, 1988). It is important to consider whether the lower drop out rate on SSRIs may have compromised the efficacy analysis as it would reduce the apparent relative efficacy of TCAs. It is very difficult to resolve this question. However most trials used last observation carried forward after two weeks treatment or completer data for efficacy analysis rather than the intention to treat sample. This is likely to reduce the difference in drop outs between the two groups used in the efficacy analysis from the already small value of 4%. This makes it unlikely that the difference in tolerability obscures a clinically significant difference in efficacy in the overall analysis. It can also be argued that a difference in drop out rate needs to be included in the analysis of clinical ‘‘effectiveness’’ as opposed to efficacy. The overall tolerability advantage does not appear equally true for all SSRIs. Fluvoxamine did not

demonstrate a significant improvement in overall drop outs or in those due to side effects compared with the TCAs. This finding agrees with clinical impression, data from Prescription Event Monitoring (Mackay et al., 1997) and from a meta-analysis of randomised controlled trials directly comparing SSRIs (Anderson 1998b). Nausea appears to be a particularly troublesome side-effect of treatment with fluvoxamine (Wakelin, 1986; Wagner et al., 1994, Mackay et al., 1997). SSRIs have been proposed as the agents of choice for the treatment of depression in elderly patients due to their more favourable tolerability profile compared with the TCAs (Dunbar, 1995; Dunner, 1994; Grimsley and Jann, 1992). However, in this meta-analysis no significant advantage to SSRIs over TCAs was observed and both were associated with a high discontinuation rate which agrees with a previous meta-analysis using different methodology (Mittmann et al., 1997). This suggests that the side-effect advantage generally accepted for SSRIs and shown by the overall analysis, cannot be assumed to apply to elderly patients to the same degree. Although the relative risk of overall drop out was reduced on SSRIs to a similar degree as that in younger patients (albeit non-significantly), the reduction in discontinuation due to adverse effects appeared considerably less marked. Systematic evidence from this metaanalysis raises doubts about whether, and if so by how much, SSRIs are better tolerated than TCAs in the elderly. Nevertheless, this result should not be over-interpreted, as the number of studies involving elderly patients was low in comparison to that in younger adults (10 vs. 85). Alongside the possible increase in efficacy noted with amitriptyline is the finding that it has a significantly higher rate of treatment discontinuation due to side effects than the SSRI comparator. Therefore, in considering clinical effectiveness, the increased efficacy of amitriptyline needs to be balanced against the increased rate of discontinuations as a high rate of treatment discontinuation compromises the overall effectiveness of a therapeutic agent. Not all TCAs may have a side-effect disadvantage, as there were fewer drop outs due to side effects on dothiepin than SSRIs. This is consistent with the clinical impression of dothiepin having a good

I.M. Anderson / Journal of Affective Disorders 58 (2000) 19 – 36

tolerability profile. However, this TCA did show a non-significantly lower efficacy than the SSRIs. General caution is required not to over-interpret the data of this meta-analysis, given the large number of subgroup analyses which are likely to show a number of significant results by chance. Errors can also be a result of selection or publication bias, which tend to favour studies with positive results. This may account for the advantage displayed by amitriptyline over SSRIs although one would have expected SSRIs to be favoured rather than the TCA given the likelihood that the effect of sponsorship is to favour the sponsored drug (Gøtzsche, 1989), in this case the SSRI. Care was taken with sensitivity analysis and exploration of publication bias, and this meta-analysis provides an evidence base for discussion. It is expected that studies with complete data, those including over 100 patients, and those that were placebo controlled, will be of better quality and less prone to publication bias. My sensitivity analysis of these categories of studies in general gave results consistent with the overall findings and only with amitriptyline is the question of publication bias seriously raised. In conclusion, this systematic review of comparative trials of SSRIs against TCAs in over 10 000 patients provides a basis for evaluating the relative clinical merits of drugs from the two groups. The consideration of individual drugs provides information that may be useful in clinical practice although caution is needed because of the danger of false positives in subgroup analysis. In addition, it remains unclear how valid it is to generalise from short-term randomised controlled trials to clinical treatment with antidepressants (e.g., Martin et al., 1997). However, naturalistic data is scanty at present and not without its own limitations and biases, making it important to use the available evidence while using care in interpretation. The conclusion that we reached in a previous meta-analysis in a smaller set of studies (Anderson and Tomenson, 1994), that amitriptyline is an antidepressant of choice when maximising efficacy is required, still holds. In contrast, the evidence for an efficacy advantage to clomipramine is lacking from this analysis. In everyday practice the SSRIs have an advantage in terms of tolerability but they are not without side effects and the advantage in terms of drop outs is modest in the

31

short-term (but could be greater in longer-term treatment). In addition in the available studies in elderly patients no advantage over TCAs could be demonstrated. The relatively small benefit in tolerability from the ‘‘objective’’ evidence of treatment discontinuation which is apparent from these studies goes some way to explaining the difficulty in providing a definitive conclusion about whether SSRIs or TCAs are more cost effective. The assumptions that have to be made and value judgements will inevitably sway the conclusion. This review could not take into account other advantages that SSRIs have been reported to have over TCAs, namely lower behavioural toxicity (Hale, 1994) and better safety in overdose (Henry et al., 1995). In considering individual SSRIs the apparent relatively poorer tolerability of fluvoxamine is consistent with data from other sources suggesting that it is not a first-line SSRI given the proven better tolerability of the other SSRIs. It is of interest that dothiepin seems well tolerated and this makes it a drug to consider if an older TCA is to be prescribed in a situation where lack of tolerability may limit treatment. However, tolerability may need to be offset against less clear efficacy and other considerations, such as toxicity in overdose (Henry et al., 1995).

References Altamura, A.C., Percudani, M., Guercetti, G., Invernizzi, G., 1989. Efficacy and tolerability of fluoxetine in the elderly: a doubleblind study versus amitriptyline. Int. Clin. Psychopharmacol. 4, 103–106. Amin, M.M., Ananth, J.V., Coleman, B.S., Darcourt, G., Farkas, T., Goldstein, B., Lapierre, Y.D., Paykel, E., Wakelin, J.S., 1984. Fluvoxamine: antidepressant effects confirmed in a placebo-controlled international study. Clin. Neuropharmacol. 7 (Suppl. 1), S316–S317. Amore, M., Bellini, M., Berardi, D., Berlinzani, L., Cervino, G., Cremonini, A., Ferrari, G., Innamorati, A., 1989. Double-blind comparison of fluvoxamine and imipramine in depressed patients. Curr. Ther. Res. 46, 815–820. Anderson, I.M., Tomenson, B.M., 1994. The efficacy of selective serotonin reuptake inhibitors in depression: a meta-analysis of studies against tricyclic antidepressants. J. Psychopharmacol. 8, 238–249. Anderson, I.M., Tomenson, B.M., 1995. Treatment discontinuation with selective serotonin reuptake inhibitors compared to

32

I.M. Anderson / Journal of Affective Disorders 58 (2000) 19 – 36

tricyclic antidepressants: a meta-analysis. Br. Med. J. 310, 1433–1438. Anderson, I.M., 1998a. SSRIs versus tricyclic antidepressants in depressed in-patients: a meta-analysis of efficacy and tolerability. Depress. Anxiety 7 (Suppl. 1), 11–17. Anderson, I.M., 1998b. A meta-analysis of controlled trials comparing SSRIs in the treatment of depression. J. Psychopharmacol. 12 (Suppl A), A20. Arminen, S.-L., Ikonen, U., Pulkkinen, M., Leinonen, E., Mahlanen, A., Koponen, H., Kourula, K., Ryyppo, J., Lehtonen, M.-L., Vartiainen, H., Lehtinen, V., Tamminen, T., 1992. Paroxetine and imipramine: a 12 week, double-blind multicentre study in hospitalized depressed patients. Nord. J. Psychiatry 46 (Suppl. 27), 27–31. Bascara, L., 1989. A double-blind study to compare the effectiveness and tolerability of paroxetine and amitriptyline in depressed patients. Acta Psychiatr. Scand. 80, 141–142. Battegay, R., Hager, M., Rauchfleisch, U., 1985. Double-blind comparative study of paroxetine and amitriptyline in depressed patients of a university psychiatric out-patient clinic (pilot study). Neuropsychobiology 13, 31–37. Beasley, Jr. C.M., Sayler, M.E., Potvin, J.H., Jr. et al., 1993. Fluoxetine versus amitriptyline in the treatment of major depression: a multicenter trial. Int. Clin. Psychopharmacol. 8, 143–149. Bersani, G., Rapisarda, V., Ciani, N., Bertolino, A., Sorge, G., 1994. A double-blind comparative study of sertraline and amitriptyline in outpatients with major depressive episodes. Hum. Psychopharmacol. 9, 63–68. Bignamini, A., Rapisarda, V., 1992. A double-blind multicentre study of paroxetine and amitriptyline in depressed out-patients. Int. Clin. Psychopharmacol. 6, 37–41. Blashki, T.G., Mowbray, R., Davies, B., 1971. Controlled trial of amitriptyline in general practice. Br. Med. J. 1, 133–138. Bouchard, J.M., Delaunay, J., Delisle, J.-P., Grassel, N., Mermberg, P.F., Molczadzki, M., Pagot, R., Richou, H., Robert, G., Ropert, R., Schuller, E., Verdeau-Pailles, J., Zarifan, E., Hopfner Petersen, H.E., 1987. Citalopram versus maprotiline: A controlled, clinical multicentre trial in depressed patients. Acta Psychiatr. Scand. 76, 583–592. Bourin, M., 1990. A double-blind comparison of paroxetine and clomipramine in depressed outpatients. Presented at the 17th CINP Kyoto, Japan. Bowden, C.L., Schatzberg, A.F., Rosenbaum, A., Contreras, S.A., Samson, J.A., Dessain, E., Sayler, M., 1993. Fluoxetine and desipramine in major depressive disorder. J. Clin. Psychopharmacol. 13, 305–310. Bramanti, P., Ricci, R.M., Roncari, R., Bilone, F., Inga, F., Teti, V., DeCristofaro, A.M., Ceccarelli, G., DiPerri, R., Candela, L., 1988. An Italian multicentre experience with fluvoxamine, a new antidepressant drug, versus imipramine. Curr. Ther. Res. 43, 718–724. Bremner, J.D., 1984. Fluoxetine in depressed patients: A comparison with imipramine. J. Clin. Psychiatr. 45, 414–419. Bressa, G.M., Brugnoli, R., Pancheri, P., 1989. A double-blind study of fluoxetine and imipramine in major depression. Int. Clin. Psychopharmacol. 4, 69–73.

Byrne, M.M., 1989. Meta-analysis of early phase II studies with paroxetine in hospitalized depressed patients. Acta Psychiatr. Scand. 80, 138–139. Chouinard, G., 1985. A double blind controlled clinical trial of fluoxetine and amitriptyline in the treatment of out-patients with major depressive disorder. J. Clin. Psychiatry 46, 32–37. ¨ ¨ J.K., BorkChristiansen, P.E., Behnke, K., Black, C.H., Ohrstrom, Rasmussen, H., Nilsson, J., 1996. Paroxetine and amitriptyline in the treatment of depression in general practice. Acta. Psychiatr. Scand. 93, 158–163. Claghorn, J.L., Earl, C.Q., Walczak, D.D., Stoner, K.A., Wong, L.F., Kanter, D., Houser, V.P., 1996. Fluvoxamine maleate in the treatment of depression: a single-center, double-blind, placebo-controlled comparison with imipramine in outpatients. J. Clin. Psychopharmacol. 16, 113–120. Cohn, C.K., Shrivastava, R., Mendels, J., Cohn, J.B., Fabre, L.F., Claghorn, J.L., Dessain, E.C., Itil, T.M., Lautin, A., 1990. Double-blind, multicenter comparison of sertraline and amitriptyline in elderly depressed patients. J. Clin. Psychiatr. 51, 28–33. Cohn, J.B., Wilcox, C., 1985. A comparison of fluoxetine, imipramine, and placebo in patients with depressive disorder. J. Clin. Psychiatr. 46, 26–31. Corne, S.J., Hall, J.R., 1989. A double-blind comparative study of fluoxetine and dothiepin in the treatment of depression in general practice. Int. Clin. Psychopharmacol. 4, 245–254. Cusack, B., Nelson, A., Richelson, E., 1994. Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology 114, 559–565. Danish University Antidepressant Group, 1986. Citalopram: Clinical effect profile in comparison with clomipramine. A controlled multicenter study. Psychopharmacology 90, 131–138. Danish University Antidepressant Group, 1990. Paroxetine: A selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicentre study. J. Affect. Disord. 18, 289–299. de Jonghe, F., Ravelli, D.P., Tuynman-Qua, H., 1991b. A randomized, double-blind study of fluoxetine and maprotiline in the treatment of major depression. Pharmacopsychiatry 24, 62–67. de Jonghe, F., Swinkels, J., Tuynman-Qua, H., 1991a. Randomized double-blind study of fluvoxamine and maprotiline in treatment of depression. Pharmacopsychiatry 21, 21–27. De Wilde, J.E.M., Doogan, D.P., 1982. Fluvoxamine and clomipramine in endogenous depression. J. Affect. Disord. 4, 249– 259. De Wilde, J.E., Mertens, C., Wakelin, J.S., 1983. Clinical trials of fluvoxamine vs clomipramine with single and three times daily dosing. Br. J. Clin. Pharmacol. 15, 427S–431S. DerSimonian, R., Laird, N., 1986. Meta-analysis in clinical trials. Control. Clin. Trial. 7, 177–188. Dick, P., Ferrero, E., 1983. A double-blind comparative study of the clinical efficacy of fluvoxamine and chlorimipramine. Br. J. Clin. Pharmacol. 15, 419S–425S. Dominguez, R.A., Goldstein, B.J., Jacobson, A.F., Steinbook, R.M., 1985. A double-blind placebo-controlled study of fluvoxamine and imipramine in depression. J. Clin. Psychiatr. 46, 84–87.

I.M. Anderson / Journal of Affective Disorders 58 (2000) 19 – 36 Donoghue, J., Tylee, A., Wildgust, H., 1996. Cross sectional database analysis of antidepressant prescribing in general practice in the United Kingdom. Br. Med. J. 313, 861–862. Doogan, D.P., Langdon, C.J., 1994. A double-blind, placebocontrolled comparison of sertraline and dothiepin in the treatment of major depression in general practice. Int. Clin. Psychopharmacol. 9, 95–100. Dowling, B., Webb, M.G.T., Halpin, C.M., Sangiwa, M.G.H., 1990. Fluoxetine: a comparative study with dothiepin. Irish J. Psychiatry Spring, 3–7. Dunbar, G.C., Cohn, J.B., Fabre, L.F., Feighner, J.P., Fieve, R.R., Mendels, J., Shrivastava, R.K., 1991. A comparison of paroxetine, imipramine and placebo in depressed out-patients. Br. J. Psychiatr. 159, 394–398. Dunbar, G.C., 1995. Paroxetine in the elderly: a comparative meta-analysis against standard antidepressant pharmacotherapy. Pharmacology 51, 137–144. Dunner, D.L., Cohn, J.B., Walshe, T., Cohn, C.K., Feighner, J.P., Rieve, R.R., Halikas, J.P., Hartford, J.T., Hearst, E.D., Settle, E.C., Menolascino, F.J., Muller, D.J., 1992. Two combined, multicentre double-blind studies or paroxetine and doxepin in geriatric patients with major depression. J. Clin. Psychiatr. 53, 57–60. Dunner, D.L., 1994. An overview of paroxetine in the elderly. Gerontology 40, 21–27. Effective Health Care, 1993. The treatment of depression in primary care. Effective Health Care Bull. 5, 1–12. Egger, M., DaveySmith, G., Schneider, M., Minder, C., 1997. Bias in meta-analysis detected by a simple, graphical test. Br.Med.J. 315, 629–634. Fabre, L.F., Scharf, M.B., Itil, T.M., 1991. Comparative efficacy and safety of nortriptyline and fluoxetine in the treatment of major depression: A clinical study. J. Clin. Psychiatr. 52, 62–67. Fabre, L., Birkhimer, L.J., Zaborny, B.A., Wong, L.F., Kapik, B.M., 1996. Fluvoxamine versus imipramine and placebo: a double blind comparison in depressed patients. Int. Clin Psychopharmacol. 11, 119–127. Fairweather, D.B., Kerr, J.S., Harrison, D.A., Moon, C.A., Hindmarch, I., 1993. A double-blind comparison of the effects of fluoxetine and amitriptyline on cognitive function in elderly depressed patients. Hum. Psychopharmacol. 8, 41–47. Fawcett, J., Zajecka, J.M., Kravitz, H.M., Edwards, J., Jeffriess, H., Scorza, E., 1989. Fluoxetine versus amitriptyline in adult out-patients with major depression. Curr. Ther. Res. 45, 821– 832. Feighner, J.P., 1985. A comparative trial of fluoxetine and amitriptyline in patients with major depressive disorder. J. Clin. Psychiatr. 46, 369–372. Feighner, J.P., Robins, E., Guse, S.B., Woodruff, R.A., Winokur, G., Munos, R., 1972. Diagnostic criteria for use in psychiatric research. Arch. Gen. Psychiatr. 26, 57–63. Feighner, J.P., Boyer, W.F., Merideth, C.H., Hendrickson, G.G., 1989a. A double-blind comparison of fluoxetine, imipramine and placebo in out-patients with major depression. Int. Clin. Psychopharmacol. 4, 127–134. Feighner, J.P., Boyer, W.F., Meredith, C.H., Hendrickson, G.G.,

33

1989b. A placebo-controlled in-patient comparison of fluvoxamine maleate and imipramine in major depression. Int. Clin. Psychopharmacol. 4, 239–244. Feighner, J.P., Cohn, J.B., 1985. Double-blind comparative trials of fluoxetine and doxepin in geriatric patients with major depressive disorder. J. Clin. Psychiatr. 46, 20–25. Fontaine, R., 1991. The efficacy and safety of sertraline versus imipramine in out-patients with major depression: a six month double-blind, parallel multicenter study. Eur. Neuropsychopharmacol. 1, P75. Gagiano, C.A., Muller, P.G.M., Fourie, J., LeRoux, J.F., 1989. The therapeutic efficacy of paroxetine: (a) an open study in patients with major depression not responding to antidepressants; (b) a double-blind comparison with amitriptyline in depressed outpatients. Acta. Psychiatr. Scand. 80, 130–131. Gasperini, M., Gatti, F., Bellini, L., Anniverno, R., Smeraldi, E., 1992. Perspectives in clinical psychopharmacology of amitriptyline and fluvoxamine: a double-blind study in depressed in-patients. Pharmacopsychiatry 26, 186–192. Geretsegger, C., Stuppaeck, C.H., Mair, M., Platz, T., Fartacek, R., Heim, M., 1995. Multicentre double blind study of paroxetine and amitriptyline in elderly depressed patients. Psychopharmacology 119, 277–281. Ginestet, D., Alby, J.M., Besancon, G., Carrier, G., Cordier, B., Degiovanni, A., Dufour, H., Ferreri, M., Leger, L., Moron, P., Pellet, J., Perivier, E., Singer, L., Ulliac, G., 1989. Fluoxetine in endogenous depression melancholia versus clomipramine. Int. Clin. Psychopharmacol. 4, 37–40. Gonella, G., Baignoli, G., Ecari, U., 1990. Fluvoxamine and imipramine in the treatment of depressive patients: a doubleblind controlled study. Curr. Med. Res. Opin. 12, 177–184. Gravem, A., Amthor, K.F., Astrup, C., Elgen, K., Gjessing, L.R., Gunby, B., Pettersen, R.D., Kyrdalen, L., Vaadal, J., Ofsti, E., Aarvold, A., 1987. A double-blind comparison of citalopram (Lu 10-171) and amitriptyline in depressed patients. Acta Psychiatr. Scand. 75, 478–486. Gøtzsche, P.C., 1989. Methodology and overt and hidden bias in reports of 196 double-blind trials of nonsteroidal antiinflammatory drugs in rheumatoid arthritis. Control. Clin. Trials 10, 31–56. Grimsley, S.R., Jann, M.W., 1992. Paroxetine, sertraline, and fluvoxamine: New selective serotonin reuptake inhibitors. Clin. Pharm. 11, 930–956. Guelfi, J.D., Dreyfus, J.F., Pichot, P., G.E.P.E.C.E.P., 1983. A double-blind controlled clinical trial comparing fluvoxamine with imipramine. Br. J. Clin. Pharmacol. 15, 411S–417S. ´ Guilibert, E., Pelicier, Y., Archambault, J.C., Chabannes, J.P., Clerc, G., Desvilles, M., Guibert, M., Pagot, R., Poisat, J.L., Thobie, Y., 1989. A double-blind, multicentre study of paroxetine versus clomipramine in depressed elderly patients. Acta Psychiatr. Scand. 80, 132–134. Guy, W., Wilson, W.H., Ban, T.A., King, D.L., Manov, G., Fjetland, I.K., 1984. Double-blind clinical trial of fluvoxamine and imipramine in patients with primary depression. Psychopharmacol. Bull. 20, 73–78. Hale, A.S., 1994. The importance of accidents in evaluating the cost of SSRIs: a review. Int. Clin. Psychopharmacol. 9, 195– 201.

34

I.M. Anderson / Journal of Affective Disorders 58 (2000) 19 – 36

Harris, B., Szulecka, T.K., Anstee, J.A., 1991. Fluvoxamine versus amitriptyline in depressed hospital out-patients: A multicentre double-blind comparative trial. Br. J. Clin. Res. 2, 89–99. Hedges, L.V., Olkin, I., 1985. Statistical Methods for Meta-Analysis, Academic Press, Orlando, FL. Heiligenstein, J.H., Tollefson, G.D., Faries, D.E., 1993. A doubleblind trial of fluoxetine, 20 mg, and placebo in out-patients with DSM-III-R major depression and melancholia. Int. Clin. Psychopharmacol. 8, 247–251. Henry, J.A., Alexander, C.A., Sener, E.K., 1995. Relative mortality from overdose of antidepressants. Br. Med. J. 310, 221–224. Hotopf, M., Lewis, G., Normand, C., 1996. Are SSRIs a costeffective alternative to tricyclics? Br. J. Psychiatry 168, 404– 409. Hotopf, M., Hardy, R., Lewis, G., 1997. Discontinuation rates of SSRIs and tricyclic antidepressants: a meta-analysis and investigation of heterogeneity. Br. J. Psychiatry 170, 120–127. Hutchinson, D.R., Tong, S., Moon, C.A.L., Vince, M., Clarke, A., 1991. A double blind study in general practice to compare the efficacy and tolerability of paroxetine and amitriptyline in depressed elderly patients. Br. J. Clin. Res. 2, 43–57. Itil, T.M., Shrivastava, R.K., Mukherjee, S., Coleman, B.S., Michael, S.T., 1983. A double-blind placebo-controlled study of fluvoxamine and imipramine in out-patients with primary depression. Br. J. Clin. Pharmacol. 15, 433S–438S. Judd, F.K., Moore, K., Norman, T.R., Burrows, G.D., Gupta, R.K., Parker, G., 1993. A multicentre double blind trial of fluoxetine versus amitriptyline in the treatment of depressive illness. Aust NZ J. Psychiatry 27, 49–55. Kasper, S., Fuger, J., Moller, H.-J., 1992. Comparative efficacy of antidepressants. Drugs 43, 11–23. Kasper, S., Voll, G., Vieira, A., Kick, H., 1990. Response to total sleep deprivation before and during treatment with fluvoxamine or maprotiline in patients with major depression – results of a double-blind trial. Pharmacopsychiatry 23, 135–142. Keegan, D., Bowen, R.C., Blackshaw, S., Saleh, S., Dayal, N., Remillard, F., Shrikhande, S., Cebrian Perez, S., Boulton, A., Richardson, S., D’Arcy, C., 1991. A comparison of fluoxetine and amitriptyline in the treatment of major depression. Int. Clin. Psychopharmacol. 6, 117–124. Kerkhofs, M., Rielaert, C., de Maertelaer, V., Linkowski, P., Czarka, M., Mendlewicz, J., 1990. Fluoxetine in major depression: efficacy, safety and effects on sleep polygraphic variables. Int. Clin. Psychopharmacol. 5, 253–260. Klok, C.J., Brouwer, G.J., VanPraag, H.M., Doogan, D., 1981. Fluvoxamine and clomipramine in depressed patients: A double-blind clinical study. Acta Psychiatr. Scand. 64, 1–11. Kuha, S., Mehtonen, O.-P., Henttonen, A., Naarala, M., 1991. The efficacy of fluoxetine versus maprotiline in depressed patients and by dose. Nord. Psykiatr. Tidsskr. 45, 109–117. Kuhs, H., Rudolf, G.A.E., 1989. A double-blind study of the comparative antidepressant effect of paroxetine and amitriptyline. Acta Psychiatr. Scand. 80, 145–146. Laakmann, G., Blaschke, D., Engel, R., Schwarz, A., 1988. Fluoxetine vs. amitriptyline in the treatment of depressed out-patients. Br. J. Psychiatry 153, 64–68.

Lader, M., 1988. Fluoxetine efficacy vs. comparative drugs: an overview. Br. J. Psychiatry 153 (Suppl. 3), 51–58. Lapierre, Y.D., Browne, M., Horn, E., Oyewumi, L.K., Sarantidis, D., Roberts, N., Badoe, K., Tessier, P., 1987. Treatment of major affective disorder with fluvoxamine. J. Clin. Psychiatry 48, 65–68. Laursen, L.A., Mikkelsen, P.L., Rasmussen, S., leFevreHonore, P., 1985. Paroxetine in the treatment of depression – a randomized comparison with amitriptyline. Acta Psychiatr. Scand. 71, 249– 255. Lepine, J.P., Wiseman, R., 1996. Treatment of severe major depression: a double-blind study of sertraline and clomipramine. Presented at the June CINP, Melbourne, Australia. Levine, S., Deo, R., Mahadevan, K., 1987. A comparative trial of a new antidepressant, fluoxetine. Br. J. Psychiatry 150, 653– 655. Loeb, C., Albano, C., Gandolfo, C., 1989. Fluoxetine versus imipramine. Int. Clin. Psychopharmacol. 4, 75–79. Lydiard, R.B., Lyle, K.L., Morton, W.A., Steele, T.E., Kellner, C., Laraia, M.T., Ballenger, J.C., 1989. Fluvoxamine, imipramine and placebo in the treatment of depressed out-patients: Effects on depression. Psychopharmacol. Bull. 25, 68–70. Lydiard, R.B., The Depression Research Group, 1996. Sertraline versus amitriptyline and quality of life: a double-blind placebocontrolled study. Presented at the June CINP, Melbourne, Australia. Mackay, F.J., Dunn, N.R., Wilton, L.V., Pearce, G.L., Freemantle, S.N., Mann, R.D., 1997. A comparison of fluvoxamine, fluoxetine, sertraline and paroxetine examined by observational cohort studies. Pharmacoepidemiol. Drug Safety 6, 235–246. Manna, V., Martucci, N., Agnoli, A., 1989. Double-blind controlled study on the clinical efficacy and safety of fluoxetine vs. clomipramine in the treatment of major depressive disorders. Int. Clin. Psychopharmacol. 4, 81–88. March, J.S., Kobak, K.A., Jefferson, J.W., Mazza, J., Greist, J.H., 1990. A double-blind, placebo-controlled trial of fluvoxamine versus imipramine in out-patients with major depression. J. Clin. Psychiatr. 51, 200–202. Martin, R.M., Hilton, S.R., Kerry, S.M., Richards, N.M., 1997. General practitioners’ perceptions of the tolerability of antidepressant drugs: a comparison of selective serotonin reuptake inhibitors and tricyclic antidepressants. Br. Med. J. 314, 646– 651. Masco, H.L., Sheetz, M.S., 1985. Double-blind comparison of fluoxetine and amitriptyline in the treatment of major depressive illness. Adv. Ther. 2, 275–283. McEntee, W., Ko, G., Richter, E., Foster, G.V., 1996. Sertraline and nortriptyline: heart rate, cognitive function and quality of life in the depressed elderly. Presented at the 20th CINP, Melbourne, Australia, 23–27 June 1996. Mittmann, N., Herrmann, N., Einarson, T.R., Busto, U.E., Lanctot, L.L., Liu, B.A., Shulman, K.I., Silver, I.L., Naranjo, C.A., Shear, N.H., 1997. The efficacy, safety and tolerability of antidepressants in late life depression: A meta-analysis. J. Affect. Disord. 46, 191–217. Moller, H.J., Haug, G., 1988. Secondary and meta-analysis of the efficacy of non-tricyclic antidepressants. Pharmacopsychiatry 2, 363–364.

I.M. Anderson / Journal of Affective Disorders 58 (2000) 19 – 36 Moller, H.-J., Berzewski, H., Eckmann, F., Gonzalves, N., Kissling, W., Knorr, W., Ressler, P., Rudolf, G.A.E., Steinmeyer, E.M., Magyar, I., Szucs, R., Szilard, J., 1993. Double-blind multicentre trial of paroxetine and amitriptyline in depressed in-patients. Pharmacopsychiatry 26, 75–78. Montgomery, S.A., Bebbington, P., Cowen, P., Deakin, W., Freeling, P., Hallstrom, C., Katona, C., King, D., Leonard, B., Levine, S., Phanjoo, A., Peet, M., Thompson, C., Thompson, C., 1993. Guidelines for treating depressive illness with antidepressants: A statement from the British Association for Psychopharmacology. J. Psychopharmacol. 7, 19–23. Montgomery, S.A., Henry, J., Macdonald, G., Dinan, T., Lader, M., Hindmarch, I., Clare, A., Nutt, D., 1994. Selective serotonin reuptake inhibitors: meta-analysis of discontinuation rates. Int. Clin. Psychopharmacol. 9, 47–53. Moon, C., Vince, M., 1996. Treatment of major depression in general practice: a double-blind comparison of paroxetine and lofepramine. Br. J. Clin. Pract. 50, 240–244. Moon, C.A.L., Jago, W., Wood, K., Doogan, D.P., 1994. A doubleblind comparison of sertraline and clomipramine in the treatment of major depressive disorder and associated anxiety in general practice. J. Psychopharmacol. 8, 171–176. Mullin, J.M., Pandita-Gunawardena, V.R., Whitehead, A.M., 1988. A double-blind comparison of fluvoxamine and dothiepin in the treatment of major affective disorder. Br. J. Clin. Pract. 42, 51–55. Nathan, R.S., Perel, J.M., Pollack, B.G., Kupfer, D.J., 1990. The role of neuropharmacologic selectivity in antidepressant action: Fluvoxamine versus desipramine. J. Clin. Psychiatr. 51, 367– 372. Nielsen, B.M., Behnke, K., Arup, P., Christiansen, P.E., Geisler, A., Ipsen, E., Maach-Moller, B., Ohrberg, S.C., 1993. A comparison of fluoxetine and imipramine in the treatment of out-patients with major depressive disorder. Acta Psychiatr. Scand. 87, 269–272. Nielsen, O.A., Mosing, I., Petersen, J.S., Larsen, T., Moller, S.E., Manniche, P.M., Skausig, O.B., 1991. Paroxetine and imipramine treatment of depressive patients in a controlled multicentre study with plasma amino acid measurements. Acta Psychiatr. Scand. 84, 233–241. Noguera, R., Altuna, R., Alvarez, E., Ayuso, J.L., Casais, L., Udina, C., 1991. Fluoxetine vs. clomipramine in depressed patients: a controlled multicentre trial. J. Affect. Disord. 22, 119–124. Norton, K.R.W., Sireling, L.I., Bhat, A.V., Rao, B., Paykel, E.S., 1984. A double-blind comparison of fluvoxamine, imipramine and placebo in depressed patients. J. Affect. Disord. 7, 297– 308. Øhrberg, S., Christiansen, P.E., Severin, B., Calberg, H., Nilakantan, B., Borup, B., Sogaard, A., Larsen, J., Loldrup, D., Bahr, B., Siebuhr, N., Gregersen, B., Jacobsen, F., Liljestrom, M., Manniche, P.M., Bech, P., 1992. Paroxetine and imipramine in the treatment of depressive patients in psychiatric practice. Acta Psychiatr. Scand. 86, 437–444. Olfson, M., Marcus, S.C., Pincus, H.A., Zito, J.M., Thompson, J.W., Zarin, D.A., 1998. Antidepressant prescribing practices of outpatient psychiatrists. Arch. Gen. Psychiatry 55, 310–316.

35

Ottevanger, E.A., 1991. The efficacy of fluvoxamine in patients with severe depression. Br. J. Clin. Res. 2, 125–132. Ottevanger, E.A., 1995. Fluvoxamine and clomipramine in depressed hospitalised patients: results from a randomised, double-blind study. L’Encephale 21, 317–321. Pakesch, G., Dossenbach, M., 1991. Depressive syndrome in a clinical trial with private practitioners. [German] OT – Wirkung und Sicherheit von Fluoxetin versus Clomipramin bei ambulanten Patienten mit einem depressiven Syndrom in einer klinischen Prufung bei niedergelassenen Arzten. Wien. Klin. Wochenschr. 103, 176–182. Pande, A.C., Sayler, M.E., 1993. Fluoxetine – A clinical and research update: Severity of depression and response to fluoxetine. Int. Clin. Psychopharmacol. 8, 243–245. Paykel, E.S., Priest, R.G., 1992. Recognition and management of depression in general practice: consensus statement. Br. Med. J 305, 98–202. ´ Pelicier, Y., Schaeffer, P., 1993. Etude multicentrique en double aveugle comparant l’efficacite´ et la tolerance de la paroxetine ´ ´ et de la clomipramine dans la depression reactionnelle du sujet ˆage. ´ L’Encephale ´ XIX, 257–261. Peters, U.H., Lenhard, P., Metz, M., 1990. Therapy of depression in the psychiatrist’s office – A double-blind multicenter study. Nervenheilkunde 9, 28–31. Poelinger, W., Haber, H., 1989. Fluoxetine 40 mg vs. maprotiline 75 mg in the treatment of out-patients with depressive disorders. Int. Clin. Psychopharmacol. 4, 47–50. Rahman, M.K., Akhtar, M.J., Savla, N.C., Sharma, R.R., Kellett, J.M., Ashford, J.J., 1991. A double-blind, randomised comparison of fluvoxamine with dothiepin in the treatment of depression in elderly patients. Br. J. Clin. Pharmacol. 45, 255–258. Ravindran, A.V., Judge, R., Hunter, B.N., Bray, J., Morton, N.H., 1997. A double-blind, multicenter study in primary care comparing paroxetine and clomipramine in patients with depression and associated anxiety. J. Clin. Psychiatry 58, 112– 118. Ravindran, A.V., Teehan, M.D., Bakish, D., Yatham, L., O’Reilly, R., Fernando, M.L., Manchanda, R., Charbonneau, Y., Buttars, J., 1995. The impact of sertraline, desipramine, and placebo on psychomotor functioning in depression. Hum. Psychopharmacol. 10, 273–281. Reimherr, F.W., Chouinard, G., Cohn, C.K., Cole, J.O., Itil, T.M., LaPierre, Y.D., Masco, H.L., Mendels, J., 1990. Antidepressant efficacy of sertraline: A double-blind, placebo- and amitriptyline-controlled, multicenter comparison study in out-patients with major depression. J. Clin. Psychiatr. 51, 18–27. Remick, R.A., Claman, J., Reesal, R., Gibson, R.E., Agbayewa, M.O., Lam, R.W., Keller, F.D., 1993. Comparison of fluoxetine and desipramine in depressed outpatients. Curr. Ther. Res. Clin. Exp. 53, 457–465. Remick, R.A., Keller, F.D., Gibson, R.E., Carter, D., 1989. A comparison between fluoxetine and doxepin in depressed patients. Curr. Ther. Res. 46, 842–848. Remick, R.A., Reesal, R., Oakander, M., Allen, J., Claman, J., Ramirez, C.E., Perry, K., Kelle, F.D., 1994. Comparison of fluvoxamine and amitriptyline in depressed outpatients. Curr. Ther. Res. Clin. Exp. 55, 243–250.

36

I.M. Anderson / Journal of Affective Disorders 58 (2000) 19 – 36

Robertson, M.M., Abou-Saleh, M.T., Harrison, D.A., Nairac, B.L., Edwards, D.R.L., Lock, T., Burns, R.A., Katona, C.L.E., 1994. A double-blind controlled comparison of fluoxetine and lofepramine in major depressive illness. J. Psychopharmacol. 8, 98–103. Ropert, R., 1989. Fluoxetine versus clomipramine in major depressive disorders. Int. Clin. Psychopharmacol. 4, 89–95. Rosenberg, C., Damsbo, N., Fuglum, E., Jacobsen, L.V., Horsgard, S., 1994. Citalopram and imipramine in the treatment of depressive patients in general practice. A Nordic multicentre clinical study. Int. Clin. Psychopharmacol. 9 (Suppl 1), 41–48. Roth, D., Mattes, J., Sheehan, K.H., Sheehan, D.V., 1990. A double-blind comparison of fluvoxamine, despiramine and placebo in out-patient with depression. Prog. Neuro-Psychopharmacol. Biol. Psychiat. 14, 929–939. Shaw, D.M., 1986. A comparison of the antidepressant action of citalopram and amitriptyline. Br. J. Psychiatr. 149, 515–517. Shillingford, J.S., Hindmarch, I., Clarke, A., Vince, M.J., 1990. A double-blind comparison of paroxetine and dothiepin on efficacy and tolerability in depressed community patients. Presented at the CINP Kyoto, Japan. Song, F., Freemantle, N., Sheldon, T.A., House, A., Watson, P., Long, A., Mason, J., 1993. Selective serotonin reuptake inhibitors: meta-analysis of efficacy and acceptability. Br. Med. J. 306, 683–687. South Wales Antidepressant Drug Trial Group, 1988. A doubleblind multi-centre trial of fluoxetine and dothiepin in major depressive illness. Int. Clin. Psychopharmacol. 3, 75–81. Spitzer, R., Endicott, J., Robins, E., 1975. Research Diagnostic Criteria, New York State Psychiatric Institute, New York. Stage, K.B., Bech, P., Gram, L.F., Kragh-Sørensen, P., Rosenberg, C., Øhrberg, S., 1998. Are in-patient depressives more often of the melancholic subtype? Acta Psychiatr. Scand. 98, 432–436. Staner, L., Kerkhofs, M., Detroux, D., Leyman, S., Linkowski, P., Mendlewicz, J., 1995. Acute, subchronic and withdrawal sleep EEG changes during treatment with paroxetine and amitriptyline: a double-blind randomized trial in major depression. Sleep 18, 470–477. Stark, P., Hardison, C.D., 1985. A review of multicenter controlled studies of fluoxetine vs imipramine and placebo in out-patients with major depressive disorder. J. Clin. Psychiatr. 46, 53–58. Steffens, D.C., Krishnan, K.R.R., Helms, M.J., 1997. Are SSRIs better than TCAs? Comparison of SSRIs and TCAs: a metaanalysis. Depress. Anxiety 6, 10–18. Stott, P.C., Blagden, M.D., Aitken, C.A., 1993. Depression and associated anxiety in primary care: a double-blind comparison

of paroxetine and amitriptyline. Eur. Neuropsychopharmacol. 3, 324–325. Stuppaeck, C.H., Geretsegger, C., Whitworth, A.B., Schubert, H., Platz, T., Konig, P., Hinterhuber, H., Fleischhacker, W., 1994. A multicentre double-blind trial of paroxetine versus amitriptyline in depressed in-patients. J. Clin. Psychopharmacol. 14, 241–246. Tamminen, T.T.A., Lehtinen, V.V., 1989. A double-blind parallel study to compare fluoxetine with doxepin in the treatment of major depressive disorders. Int. Clin. Psychopharmacol. 4, 51–56. Taneri, Z., Kohler, R., 1989. Fluoxetine versus nomifensine in out-patients with neurotic or reactive depression disorder. Int. Clin. Psychopharmacol. 4, 56–61. Thompson, C., 1991. Sertraline in primary care setting. In: Racagni, G. (Ed.), Biological Psychiatry, Elsevier, pp. 863– 865. Thompson, C., Thompson, C.M., 1989. The prescribing of antidepressants in general practice. II. A Placebo-controlled trial of low-dose dothiepin. Hum. Psychopharmacol. 4, 191–204. Tignol, J., Stoker, M.J., Dunbar, G.C., 1992. Paroxetine in the treatment of melancholia and severe depression. Int. Clin. Psychopharmacol. 7, 91–94. Timmerman, L., De Beurs, P., Tan, B.K., Leijnse-Ybema, H., Sanchez, C., Hopfner Petersen, H.E., Cohen-Stuart, M.H., 1987. A double-blind comparative clinical trial of citalopram vs. maprotiline in hospitalized depressed patients. Int. Clin. Psychopharmacol. 2, 239–253. Tollefson, G.D., Greist, J.H., Jefferson, J.W., Heiligenstein, J.H., Sayler, M.E., Tollefson, S.L., Koback, K., 1994. Is baseline agitation a relative contraindication for a selective serotonin reuptake inhibitor: a comparative trial of fluoxetine versus imipramine. J. Clin. Psychopharmacol. 14, 385–391. Upward, J.W., Edwards, J.G., Goldie, A., Waller, D.G., 1988. Comparative effects of fluoxetine and amitriptyline on cardiac function. Br. J. Clin. Pharmacol. 26, 399–402. Wagner, W., Zaborny, B.A., Gray, T.E., 1994. A review of its safety profile in world-wide studies. Int. Clin. Psychopharmacol. 9, 223–227. Wakelin, J.S., 1986. Fluvoxamine in the treatment of the older depressed patient; double-blind, placebo-controlled data. Int. Clin. Psychopharmacol. 1, 221–230. Young, J.P.R., Coleman, A., Lader, M.H., 1987. A controlled comparison of fluoxetine and amitriptyline in depressed outpatients. Br. J. Psychiatr. 151, 337–340.