Amitriptyline for Inpatients and SSRIs for Outpatients with Depression? Systematic Review and Meta-Regression Analysis

Background: Although the selective serotonin reuptake inhibitors (SSRIs) are widely used as first-line agents in depression, amitriptyline, a reference tricyclic (TCA) agent, has the edge in terms of efficacy over control antidepressants (ADs), but it is not clear whether this advantage can be attributed to a more favourable profile in inpatients, but not in outpatients, with depression. The aim of this study was to investigate the contribution of study setting on outcome in clinical trials comparing amitriptyline with any other AD. Methods: A systematic review and meta-regression analysis of amitryptiline randomised clinical trials was carried out. The electronic search yielded 181 randomised clinical trials, 47 % enrolling inpatients and 53 % outpatients with depression. Results: Both on a dichotomous and continuous outcome, amitriptyline was more effective than control agents in inpatients [Peto odds ratio (OR): 1.22, 95 %, Confidence Interval (CI): 1.04, 1.42; Standardised Mean Difference (SMD): 0.28, 95 %, CI: 0.08, 0.46], but not in outpatients (Peto OR: 1.01, 95 %, CI: 0.88, 1.17; SMD: 0.10, 95 % CI: -0.02, 0.23). Among inpatients amitriptyline was significantly more effective than TCA and nonsignificantly more effective than the SSRIs. Among outpatients no statistically significant differences emerged between amitriptyline and TCA and between amitriptyline and the SSRIs. Amitriptyline was less well tolerated than control agents in outpatients (Peto OR: 0.90, 95 %, CI: 0.81, 0.99), but not in inpatients (Peto OR: 1.09, 95 % CI: 0.95, 1.25). Conclusions: These data suggest that a reasonable approach could be the first-line prescription of newer agents in the routine outpatient care of depressive subjects, and the use of amitriptyline in inpatients with severe depression.

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Appendix 1 Characteristics of included studies

Study	Methods	Participants	Control intervention	Outcomes	Notes
Aberg 1977	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: presence of depression, HMD 25+ and Beck 12+ Age: 49 mean Country: Sweden Setting: inpatients	amoxapine	responders dropouts	quality rating: 22
Altamura 1989	Double blind RCT Active treatment: 5 weeks	Inclusion criteria: DSM III major depression, HMD 17+ Age: 60-83 Country: Italy Setting: inpatients	trazodone	mean score at end point dropouts	quality rating: 17
Altamura 1989a	Double blind RCT Active treatment: 5 weeks	Inclusion criteria: DSM III major depression, HMD 18+ Age: 65+ Country: Italy Setting: inpatients	fluoxetine	dropouts	quality rating: 16
Amin 1973	Double blind RCT Active treatment: 8 weeks	Inclusion criteria: patients with depression Age: 19-62 Country: Canada Setting: inpatients	maprotiline	responders dropouts	quality rating: 17
Amin 1978	Double blind RCT Active treatment: 3 weeks	Inclusion criteria: endogenous and neurotic depression Age: 24-56 Country: Canada Setting: outpatients	desipramine	dropouts	quality rating: 13
Ather 1985	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: primary diagnosis of depression, HMD 14+ Age: 59+ Country: UK Setting: in- and outpatients	trazodone	responders dropouts	quality rating: 22
Balestrieri 1971	Double blind RCT Active treatment: 3 weeks	Inclusion criteria: patients suitable for antidepressant treatment Age: 52.9 mean Country: Italy Setting: inpatients	imipramine and maprotiline	dropouts	quality rating: 20
Battegay 1985	Double blind RCT Active treatment: 7 weeks	Inclusion criteria: DSM III endogenous and reactive depression, HMD 20+ Age: 18-60 Country: Switzerland Setting: outpatients	paroxetine	responders dropouts	quality rating: 19
Beckmann 1975	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: Feighner primary affective disorder, unipolar Age: 20-72 Country: US Setting: inpatients	imipramine	responders dropouts	quality rating: 9
Bennie 1976	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: patients with anxiety-depressive states Age: 18-65 Country: UK Setting: outpatients	nortriptyline/ flu-phenazine	mean score at end point dropouts	quality rating: 16
Bersani 1994	Double blind RCT Active treatment: 8 weeks	Inclusion criteria: DSM III R major depression, HMD 22+ Age: 21-69 Country: Italy Setting: outpatients	sertraline	mean score at end point dropouts	quality rating: 15
Bianchi 1971	Double blind RCT Active treatment: 5 weeks	Inclusion criteria: Slater and Roth criteria of neurotic and endogenous depression Age: 50 mean Country: Australia Setting: in and outpatients	doxepin	responders dropouts	quality rating: 15
Bignamini 1992	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM III major depression, HMD 18+ Age: 18-70 Country: Italy Setting: outpatients	paroxetine	responders dropouts	quality rating: 19
Blacker 1988	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM III major depression, HMD 17+ Age: 18-65 Country: UK Setting: family practice	dothiepin and mianserin and trazodone	mean score at end point (trazodone-amitriptyline) dropouts (combination-amitriptyline)	quality rating: 23
Botros 1989	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: primary depressive illness, HMD 17+ Age: 18-80 Country: UK Setting: outpatients	trazodone	dropouts	quality rating: 18
Browne 1969	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: depressive illness Age: 40 - 69 Country: UK Setting: in and outpatients	imipramine/ perphenazine	responders dropouts	quality rating: 16
Burke 1967	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: depressive syndrome requiring hospitalisation Age: 20+ Country: Australia Setting: inpatients	trimipramine	responders	quality rating: 16
Burrows 1980	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: moderate to severe depression requiring hospitalisation Age: 16+ Country: Australia Setting: inpatients	amoxapine	responders dropouts	quality rating: 17
Burt 1962	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: female hospitalised patients with ”primary affective alteration” Age: 30 - 70 Country: Australia Setting: inpatients	imipramine	responders	quality rating: 20
Byrne 1989	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: endogenous depression, HMD 23+ Age: 18-65 Country: Belgium, France, UK Setting: inpatients	paroxetine	dropouts	quality rating: 17
Carman 1991	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM III major depression, HMD 17+ Age: 18+ Country: US Setting: outpatients	mianserin	dropouts	quality rating: 20
Carney 1984	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: depression, HMD 14+ Age: not clear Country: Ireland Setting: in- and outpatients	trazodone	responders dropouts	quality rating: 13
Chouinard 1985	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: RDC major depressive disorder, HMD 20+, Raskin greater than Covi Age: 24-59 Country: Canada Setting: outpatients	fluoxetine	dropouts	quality rating: 20
Christiansen 1996	Double blind RCT Active treatment: 8 weeks	Inclusion criteria: patients with depression, HMD 15+ Age: 18-65 Country: Denmark Setting: family practice	paroxetine	responders mean score at end point dropouts	quality rating: 21
Click 1982	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: depressive patients, HMD 25+, Raskin 8+, Zung 50+ Age: 18-60 Country: US Setting: outpatients	amoxapine	responders dropouts	quality rating: 15
Cohn 1990	Double blind RCT Active treatment: 8 weeks	Inclusion criteria: DSM III R major depressive episode, HMD 18+, Raskin greater than Covi Age: 65+ Country: US Setting: outpatients	sertraline	dropouts	quality rating: 16
Cournoyer 1987	Double blind RCT Active treatment: 3 weeks	Inclusion criteria: DSM III and RDC criteria major depressive episode, unipolar and bipolar, HMD 20+ Age: 26-72 Country: Canada Setting: inpatients	trimipramine	mean score at end point dropouts	quality rating: 18
Dahl 1981	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: depressive disorder, ‘masked depression’ Age: 20-68 Country: Sweden Setting: family practice	dothiepin	dropouts	quality rating: 16
Daly 1979	Double blind RCT Active treatment: 3 weeks	Inclusion criteria: depression Age: 18-65 Country: Ireland Setting: inpatients	mianserin	dropouts	quality rating: 15
De Ronchi 1998	Double blind RCT Active treatment: 10 weeks	Inclusion criteria: DSM III R major depressive disorder, HMD 16+ Age: 60+ Country: Italy Setting: outpatients	fluoxetine	mean score at end point dropouts	quality rating: 25
Deering 1974	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: ‘change of mood which exceeded the normal variation in mood by virtue of its severity and duration’ Age: 40 average Country: UK Setting: family practice	dothiepin	responders mean score at end point dropouts	quality rating: 19
Del Zompo 1990	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM III major depression, HMD 16+ Age: 47 mean Country: Italy Setting: outpatients	minaprine	responders mean score at end point dropouts	quality rating: 23
Delaunay 1978	Double blind: not clear RCT, allocation concealment may be inadequate Active treatment: 3 weeks	Inclusion criteria: patients who need antidepressant treatment Age: 18-75 Country:France Setting: outpatients	dothiepin	responders dropouts	quality rating: 20
Dell 1977	Double blind RCT Active treatment: 3 weeks	Inclusion criteria: depression of sufficient severity as to warrant treatment with antidepressant drugs Age: 45 average Setting: family practice	maprotiline	dropouts	quality rating: 19
Demyttenaere 1998	Double blind RCT Active treatment: 9 weeks	Inclusion criteria: DSM III R major depression, unipolar, HMD 15+ Age: 18-60 Country: Belgium Setting: outpatients	fluoxetine	responders mean score at end point dropouts	quality rating: 20
Donlon 1981	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: RDC endogenous depression, HMD 25+, Raskin 8+, Zung 50+ Age: 18-60 Country: US Setting: outpatients	amoxapine	responders dropouts	quality rating: 19
Doongaji 1993	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM III major depression, HMD 20+, CGI 4+ Age: 20-65 Country: India Setting: in- and outpatients	lofepramine	responders dropouts	quality rating: 24
Dorman 1980	Double blind RCT Active treatment: 5 weeks	Inclusion criteria: patients whose condition was judged appropriate for antidepressant treatment Age: 18-60 Country: UK Setting: outpatients	dothiepin	mean scores at end point dropouts	quality rating: 21
Dorn 1980	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: patients with depression Age: 65+ Country: Germany Setting: outpatients	lofepramine	responders mean score at end point dropouts	quality rating: 17
Edwards 1996	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM IIIR depression, HMD 17+ Age: 18-70 Country: UK, Ireland Setting: outpatients	minaprine	dropouts	quality rating: 32
Fawcett 1989	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM III major depression, unipolar, HMD 20+ Age: 18+ Country: US Setting: outpatients	fluoxetine	responders mean score at end point dropouts	quality rating: 21
Feighner 1983	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: Feighner and RDC criteria for major depressive disorder, HMD 19+ Age: 40 average Country: US Setting: outpatients	mianserin	responders dropouts	quality rating: 18
Ferrari 1987	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: DSM III major depression, without psychotic features Age: 18-70 Country: Italy Setting: inpatients	viloxazine	dropouts	quality rating: 17
Forrest 1964	RCT, not blind Active treatment: 2 weeks	Inclusion criteria: depressive patients Age:20-80 Country: UK Setting: in and outpatients	nortriptyline	responders	quality rating: 14
Forrest 1975	Double blind RCT Active treatment: 3 weeks	Inclusion criteria: patients suitable for antidepressant treatment, reactive depression Age: up to 60 Country: UK Setting: family practice	maprotiline	dropouts	quality rating: 13
Freed 1999	Double blind RCT Active treatment: 9 weeks	Inclusion criteria: patients with MADRS 20+ Age: 19-85 Country: Australia Setting: family practice	paroxetine	mean score at end point dropouts	quality rating: 28
Fruensgaard 1979	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: endogenous depression Age: 22-71 Country: Denmark Setting: inpatients	amoxapine	responders dropouts	quality rating: 13
Gasperini 1992	Double blind RCT Active treatment: 7 weeks	Inclusion criteria: DSM III R major depressive episode Age: 51 average Country: Italy Setting: inpatients	fluvoxamine	dropouts	quality rating: 17
Geretsegger 1995	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM III R major depressive episode, HMD 18+ Age: 65+ Country: Germany and Austria Setting: inpatients for at least three weeks	paroxetine	responders dropouts	quality rating: 19
Goldberg 1977	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: neurotic depression, HMD 20+, Raskin 7+ Age: 37.8 average Country: US Setting: outpatients	imipramine	responders	quality rating: 20
Goldberg 1980	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: New York University criteria of neurotic depression, HMD 18+, Raskin 7+ Age: 18-60 Country: US Setting: outpatients	trazodone	responders dropouts	quality rating: 19
Goldstein 1969	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: two or more target symptoms of anxiety and depression of at least moderate severity Age: 21+ Country: US Setting: outpatients	doxepin	responders dropouts	quality rating: 15
Gravem 1987	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: patients with severe depression Age: 19-74 Country: Norway Setting: in and outpatients	citalopram	responders dropouts	quality rating: 20
Grof 1974	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: Robins criteria of primary depression Age: 25-65 Country: Canada Setting: in- and outpatients	doxepin	dropouts	quality rating: 16
Guelfi 1989	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM III dysthymic disorder, MADRS 20+, FDA criteria for anxiety Age: 20 - 65 Country: France Setting: outpatients	tianeptine	responders mean score at end point dropouts	quality rating: 27
Guy 1983	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: RDC major, minor, intermittent depressive disorder, HMD 19+ Age: 18-65 Country: US Setting: inpatients	mianserin	responders dropouts	quality rating: 24
Harding 1973	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: primary depression, African or predominantly African origin Age: 15-70 Country: Jamaica Setting: outpatients	clomipramine	dropouts	quality rating: 16
Harris 1991	Double blind RCT Active treatment: 6 months	Inclusion criteria: DSM III major depressive episode, HMD 17+ Age: 18-65 Country: UK Setting: outpatients	fluvoxamine	responders mean score at end point dropouts	quality rating: 18
Hegerl 1997	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM-III-R major depressive episode Age: unclear Country: Germany and Hungary Setting: inpatients	sertraline	dropouts	quality rating: 14
Hekimian 1978	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: moderate to severe depressive illness, Raskin 8+ Age: 18-65 Country: US Setting: outpatients	amoxapine	dropouts	quality rating: 20
Hosak 2000	No blind RCT Active treatment: 6 months	Inclusion criteria: ICD-10 depressive episode Age: 44.5 mean Country: Czech Republic Setting: outpatients	citalopram and fluoxetine	dropouts	quality rating:20
Hutchinson 1992	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM III major depressive episode, HMD 18+ Age: 65+ Country:UK Setting: family practice	paroxetine	responders dropouts	quality rating: 20
Invernizzi 1994	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM III depressive disorder, HMD 18+ Age: 18-70 Country: Italy Setting: in and outpatients	tianeptine	responders dropouts	quality rating: 24
James 1982	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: primary diagnosis of depression requiring antidepressants, HMD 25+, Beck 12+ Age: 16-65 Country: Ireland Setting: inpatients	amoxapine	responders dropouts	quality rating: 19
Jaskari 1977	Double blind RCT Active treatment: 3 weeks	Inclusion criteria: depressive illness Age: 17-64 Country: Finland Setting: inpatients	mianserin	dropouts	quality rating: 16
Judd 1993	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM III R major depressive disorder, HMD 17+ Age: 21-63 Country: Australia Setting: in- and outpatients	fluoxetine	mean score at end point dropouts	quality rating: 20
Kamijima 1997	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM IV Major Depression, 16+ HMD Age: not clear Country: Japan Setting: in and outpatients	sertraline	dropouts	quality rating: 17
Kampman 1978	Double blind RCT Active treatment: 8 weeks	Inclusion criteria: clinical depression Age: 18-66 Country: Finland Setting: outpatients	clomipramine	responders mean score at end point dropouts	quality rating: 21
Kaumeier 1980	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: depressive illness, HMD 25+, Beck 12+ Age: 50 average Country: Germany Setting: inpatients	amoxapine	responders dropouts	quality rating: 20
Kay 1974	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: depressed women with persistent depressive symptoms of more than one month’s duration Age: 18+ Country: Australia Setting: family practice	maprotiline	mean score at end point dropouts	quality rating: 15
Kerr 1984	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: ICD IX primary depressive illness Age: 21-77 Country: UK Setting: inpatients	trazodone	responders dropouts	quality rating: 15
Khan 1981	Single blind RCT (doctors blind to treatments) Active treatment: 4 weeks	Inclusion criteria: depressive illness requiring antidepressants Age: 60+ Country: UK Setting: outpatients	dothiepin	dropouts	quality rating: 14
Khan 1982	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: severe depressive illness with suicidal ideation Age: 18-65 Country: UK Setting: inpatients	mianserin	dropouts	quality rating: 15
Kiloh 1979	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: endogenous depression as defined by Slater and Roth, HMD 14-37 Age: not clear, adults Country: Australia Setting: inpatients and outpatients	viloxazine	responders dropouts	quality rating: 15
Klieser 1988	Double blind RCT Active treatment: 3 weeks	Inclusion criteria: DSM III major depressive disorder Age: 40 average Country: Germany Setting: inpatients	trazodone	responders mean score at end point dropouts	quality rating: 15
Kocsis 1986	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: SADS and RCD diagnosis of major depressive disorder, unipolar and bipolar Age: adults Country: US Setting: inpatients	imipramine	responders dropouts	quality rating: 18
Kuhs 1989	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM III major depression, HMD 18+ Age: 18-65 Country: Germany Setting: inpatients	paroxetine	mean score at end point dropouts	quality rating: 14
Kyle 1998	Double blind RCT Active treatment: 8 weeks	Inclusion criteria: DSM III R major depression, MADRS 22+, MMSE 24+ Age: 65+ Country: UK Setting: family practice	citalopram	responders dropouts	quality rating: 27
Laakmann 1988	Double blind RCT Active treatment: 5 weeks	Inclusion criteria: depressive syndromes, HMD 17+, Raskin 8+ Age: 19-74 Country: Germany Setting: outpatients	fluoxetine	mean score at end point dropouts	quality rating: 20
Laakmann 1991	Double blind RCT Active treatment: 5 weeks	Inclusion criteria: depressive patients, HMD 17+, Raskin 8+ Age: 19-74 Country: Germany Setting: outpatients	fluoxetine	mean score at end point dropouts	quality rating: 20
Lapierre 1980	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: Feighner criteria of primary affective disorder, agitated and retarded depression Age: 18-55 Country: Canada Setting: in- and outpatients	trazodone	dropouts	quality rating: 12
Lauritsen 1974	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: patients requiring antidepressants Age: 16+ Country: Sweden, Finland, Holland, Denmark Setting: inpatients	maprotiline	responders dropouts	quality rating: 17
Laursen 1985	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: ICD 8 Manic-depressive psychosis, HMD 15+ Age: 35-81 Country: Denmark Setting: inpatients with outpatient followup	paroxetine	responders mean score at end point dropouts	quality rating: 19
Leahy 1967	Double blind RCT Active treatment: 3 months	Inclusion criteria: marked and persistent mood depression of at least 2 weeks’ duration Age: 25 - 70 Country: UK Setting: inpatients	nortriptyline	dropouts	quality rating: 12
Lehmann 1982	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: RDC major unipolar depression, HMD 20+ Age: 18-69 Country: US Setting: inpatients	nortriptyline	mean score at end point dropouts	quality rating: 16
Lennox 1978	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: depressed patients requiring antidepressants Age: 18-68 Country: UK Setting: family practice	viloxazine	dropouts	quality rating: 18
Levin 1974	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: patients with depressive illness requiring antidepressants Age: not clear Country: South Africa Setting: inpatients and outpatients	maprotiline	responders dropouts	quality rating: 12
Lipsedge 1971	Double blind RCT Active treatment: 3 months	Inclusion criteria: primary depressive illness with anxiety Age: 16-73 Country: UK Setting: outpatients	dothiepin	responders	quality rating: 16
Loga 1992	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM III R recurrent major depression, bipolar depression, depressive neurosis Age: 18-70 Country: Yugoslavia Setting: inpatients	dothiepin	dropouts	quality rating: 19
Loo 1988	Double blind RCT Active treatment: 8 weeks	Inclusion criteria: DSM III depressive syndrome or dysthymic disorder and chronic alcoholism, MADRS 20+ Age: 38 average Country: France Setting: in and outpatients	tianeptine	dropouts	quality rating: 21
Lydiard 1997	Double blind RCT Active treatment: 8 weeks	Inclusion criteria: DSM III R major depression, HMD 18+, CGI 3+ Age: adults Country: US Setting: outpatients	sertraline	dropouts	quality rating: 16
Magnus 1977	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: depressive patients requiring antidepressants Age: 18-65 Country: UK Setting: outpatients	nortriptyline/ fluphenazine	dropouts	quality rating: 18
Marais 1974	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: endogenous depression requiring antidepressants Age: 31-70 Country: South Africa Setting: in and outpatients	maprotiline	responders dropouts	quality rating: 17
Marchesi 1998	Double blind RCT Active treatment: 10 weeks	Inclusion criteria: DSM III R major depression, HMD 16+ Age: 43 average Country: Italy Setting: outpatients	fluoxetine	mean score at end point dropouts	quality rating: 29
Mariategui 1978	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: endogenous and neurotic depression requiring antidepressants Age: 16-65 Country: Perù Setting: outpatients	lofepramine	responders mean score at end point dropouts	quality rating: 14
Marneros 1979	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: Schneider and Spitzer criteria of endogenous depression Age: 24-65 Country: German Setting: inpatients	lofepramine	responders dropouts	quality rating: 19
Masco 1985	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: major depressive illness, HMD 20+, Raskin greater than Covi Age: 51 average Country: US Setting: outpatients	fluoxetine	responders dropouts	quality rating: 21
Mason 1990	Double blind RCT Active treatment: 8 weeks	Inclusion criteria: DSM III major depressive disorder, HMD 20+ Age: 46 average Country: US Setting: inpatients and outpatients	amoxapine	responders dropouts	quality rating: 19
McCallum 1975	Double blind RCT Active treatment: 3 weeks	Inclusion criteria: patients with depression Age: 42 average Country: Australia Setting: outpatients	maprotiline	mean score at end point dropouts	quality rating: 18
McClelland 1979	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: ICD endogenous or neurotic depression Age: 55 average Country: UK Setting: inpatients and outpatients	lofepramine	responders mean score at end point dropouts	quality rating: 20
McConaghy 1965	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: patients suffering from depression Age: adults Country: Australia Setting: outpatients	protriptyline	responders	quality rating: 18
Melo de Paula 1977	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: patients with depression, HMD 25+, Beck 12+ Age: 48 average Country: Brazil Setting: inpatients	amoxapine	dropouts	quality rating: 19
Mendels 1968	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: patients with depression Age: 54 average Country: US Setting: in and outpatients	nortriptyline	dropouts	quality rating: 20
Mendlewicz 1980	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: Feighner criteria of primary affective disorder, unipolar or bipolar Age: 40 average Country: Belgium Setting: inpatients	dothiepin	responders dropouts	quality rating: 15
Mendlewicz 1982	RCT, not blind (not clear) Active treatment: 4 weeks	Inclusion criteria: Feighner criteria of primary affective disorder Age: 29-68 Country: Belgium Setting: inpatients	mianserin	responders dropouts	quality rating: 21
Metha 1980	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: depressive illness requiring antidepressants Age: 41 average Country: UK Setting: family practice	mianserin	responders mean score at end point dropouts	quality rating: 15
Mindham 1977	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: depression, patients suitable for treatment with tricyclic antidepressants Age: 19-75 Country: UK Setting: family practice	maprotiline	responders dropouts	quality rating: 17
Moller 1993	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM III major depressive disorder, HMD 18+ Age: not clear Country: Germany, Hungary Setting: inpatients	paroxetine	mean score at end point dropouts	quality rating: 22
Moller 1995	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: DSM III major depressive episode, HMD 18+ Age: 18-65 Country: Germany Setting: inpatients	mianserin	responders dropouts	quality rating: 21
Moller 1998	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM III R major depression, single episode or recurrent, HMD 21+ Age: 18-75 Country: Germany, Hungary, Czech Republic Setting: inpatients	sertraline	dropouts	quality rating: 31
Moller 2000	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM III R major depression, single episode or recurrent, HMD 21+ Age: 18-75 Country: Germany Setting: outpatients and family practice	sertraline	dropouts	quality rating: 27
Monteleone 1994	RCT Double-blind (not clear) Active treatment: 5 weeks	Inclusion criteria: male subjects, DSM III R major depression, HMD 18+ Age: 60+ Country: Italy Setting: outpatients	mianserin	mean score at end point dropouts	quality rating: 12
Montgomery 1980	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: Feighner criteria of primary depressive illness Age: 42 average Country: UK Setting: inpatients	maprotiline	responders mean score at end point dropouts	quality rating: 18
Muller-Oerlingausen 1979	Double blind RCT Active treatment: 3 weeks	Inclusion criteria: depressive syndrome requiring antidepressants, HMD 16+ Age: 20 - 65 Country: Germany Setting: inpatients	viloxazine	dropouts	quality rating: 19
Murphy 1978	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: patients with a primary diagnosis of depression Age: 18-70 Country: UK Setting: family practice	mianserin	dropouts	quality rating: 21
Murphy 1980	Double blind RCT Active treatment: 8 weeks	Inclusion criteria: primary diagnosis of depression Age: 18-65 Country: UK Setting: family practice	trazodone	dropouts	quality rating: 13
Naftulin 1972	Double blind RCT Active treatment: 5 weeks	Inclusion criteria: mixed anxiety-depression Age: 19-51 Country: US Setting: outpatients	doxepin/perphenazine	responders dropouts	quality rating: 10
Nelson 1982	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: RDC major depressive disorder Age: 19-69 Country: US Setting: inpatients	imipramine	dropouts	quality rating: 11
Nieto 1973	Double blind RCT, allocation concealment may be inadequate Active treatment: 4 weeks	Inclusion criteria: depressive episode Age: 14-58 Country: Mexico Setting: outpatients	maprotiline	responders dropouts	quality rating: 11
Nugent 1979	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: female depressive patients requiring antidepressants Age: 60+ Setting: inpatients	viloxazine	mean score at end point dropouts	quality rating: 19
Okasha 1976	Double blind RCT Active treatment: 3 weeks	Inclusion criteria: patients suffering from depression Age: 10-60 Country: Egypt Setting: outpatients	maprotiline	responders dropouts	quality rating: 17
Peters 1990	Double blind RCT Active treatment: 5 weeks	Inclusion criteria: ICD 9 endogenous depression, unipolar or bipolar, HMD 17+, Raskin 8+ and greater than Covi Age: 25-63 Country: Germany Setting: outpatients	fluoxetine	responders mean score at end point dropouts	quality rating: 16
Petrie 1982	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: ICD manic-depression of the depressed type, involuntary melancholia, HMD 20+, Neurotic/Endogenous Rating Scale 6+ Age: 18 - 60 Country: US Setting: outpatients	viloxazine	responders dropouts	quality rating: 19
Preskorn 1991	Double blind RCT Active treatment: 6 week	Inclusion criteria: DSM III major depressive disorder, HMD 20+ Age: 18+ Country: US Setting: outpatients	fluoxetine	dropouts	quality rating: 19
Prusoff 1981	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: RDC major depression, Raskin 7+ Age: 18-65 Country: US Setting: outpatients	amoxapine	responders dropouts	quality rating: 21
Pugh 1982	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: depressive illness requiring antidepressants Age: 15-75 Country: UK Setting: outpatients	lofepramine	dropouts	quality rating: 14
Quadri 1980	Double blind RCT, allocation concealment may be inadequate Active treatment: 4 weeks	Inclusion criteria: Feighner criteria of endogenous depression, HMD 20+ Age: 22-52 Country: India Setting: inpatients	imipramine	responders dropouts	quality rating: 12
Querol 1970	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: depressive syndrome Age: 15-66 Country: Perù Setting: outpatients	doxepin	responders dropouts	quality rating: 15
Rabkin 1984	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: RDC major depressive disorder, HMD 18+ Age: 18-65 Country: US Setting: in and outpatients	mianserin	mean score at end point	quality rating: 19
Rampello 1995	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM III R major depression, unipolar or bipolar, HMD 20+ Age: 18-62 Conutry: Italy Setting: outpatients	amineptine	mean score at end point dropouts	quality rating: 19
Rees 1976	Single blind RCT Active treatment: 4 weeks	Inclusion criteria: mild to moderate depression Age: range not clear Country: UK Setting: outpatients	dothiepin	responders dropouts	quality rating: 17
Rego 1974	Single blind RCT Active treatment: 4 weeks	Inclusion criteria: patients requiring antidepressants Age: 26-67 Country: Spain Setting: in and outpatients	maprotiline	responders	quality rating: 12
Reimherr 1990	Double blind RCT Active treatment: 8 weeks	Inclusion criteria: DSM III major depression, HMD 18+, Raskin greater than Covi Age: 18-65 Country: US, Canada Setting: outpatients	sertraline	mean score at end point dropouts	quality rating: 25
Remick 1994	Double blind RCT Active treatment: 7 weeks	Inclusion criteria: DSM III R major depressive disorder, HMD 20+ Age: 18-65 Country: Canada Setting: outpatients	fluvoxamine	mean score at end point dropouts	quality rating: 23
Richmond 1964	Blind RCT (all assessment were made blindly, but not clear whether patients were blind) Active treatment: 3 weeks	Inclusion criteria: patients with depression requiring antidepressants Age: not clear Country: UK Setting: outpatients	imipramine	responders	quality rating: 8
Rickels 1970	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: neurotic depressed patients Age: 44 average Country: US Setting: family practice, outpatients	trimipramine	dropouts	quality rating: 18
Rickels 1972	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: neurotic depression Age: 43 average Country: US Setting: family practice, outpatients	doxepin/perphenazine	dropouts	quality rating: 16
Rickels 1974	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: non-psychotic depression Age: 21-65 Country: US Setting: family practice, outpatients	clomipramine	dropouts	quality rating: 19
Rickels 1982	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: non-psychotic depression, HMD 18+, Raskin 8+, Feighner 15+ Age: 41 average Country: US Setting: family practice, outpatients	doxepin/perphenazine	dropouts	quality rating: 21
Rickels 1982a	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM III major depressive disorder Age: 40 average Country: US Setting: family practice, outpatients	trazodone	responders dropouts	quality rating: 18
Rickels 1985	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: Feighner criteria for major depression, HMD 18+, Raskin 8+, Covi less or equal than Raskin Age: 39 average Country: US Setting: outpatients	doxepin	dropouts	quality rating: 23
Rose 1965	RCT, not double blind Active treatment: 4 weeks	Inclusion criteria: primary depressive disorder Age: less than 65 Country: UK Setting: in and outpatients	nortriptyline	responders dropouts	quality rating: 9
Rush 1988	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: unipolar major non-psychotic depression Age: 35 average Country: US Setting: inpatients	nortriptyline	responders	quality rating: 13
Rush 1989	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: RDC criteria of nonpsychotic major depressive disorder Age: 18-65 Country: US Setting: outpatients	desimipramine	responders dropouts	quality rating: 16
Rybakowski 1991	RCT, not double-blind Active treatment: 4 weeks	Inclusion criteria: female patients with unipolar depressive disorder Age: 23-66 Country: Poland Setting: impatients	imipramine	responders	quality rating: 15
Sandifer 1965	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: female patients with depression, HMD 23+ Age: 40-59 Country: US Setting: inpatients	imipramine	responders dropouts	quality rating: 21
Sedman 1977	Double blind RCT Active treatment: 5 weeks	Inclusion criteria: depressive illness requiring antidepressants Age: 52 average Country: UK Setting: inpatients	viloxazine	responders dropouts	quality rating: 22
Sethi 1979	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: patients suffering from depression, HMD 25+, Beck 12+ Age: 43 average Country: India Setting: inpatients	amoxapine	responders dropouts	quality rating: 18
Shaw 1986	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM III major depressive illness, HMD 18+ Age: 18-70 Country: UK Setting: in and outpatients	citalopram	mean score at end point dropouts	quality rating: 17
Shipley 1985	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: RDC depression, HMD 30+ Age: 41 average Country: US Setting: inpatients	desipramine	responders mean score at end point dropouts	quality rating: 14
Silverstone 1977	Double blind RCT Active treatment: 3 weeks	Inclusion criteria: symptoms of depression of sufficient severity to be treated with antidepressants Age: 45 average Country: UK Setting: family practice	maprotiline	dropouts	quality rating: 16
Sims 1980	Double blind RCT Active treatment: 5 weeks	Inclusion criteria: depressive illness Age: 18-65 Country: UK Setting: inpatients	maprotiline	mean score at end point dropouts	quality rating: 18
Sinclair 1975	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: anxiety/depression syndrome requiring antidepressants Age: 65+ Country: UK Setting: family practice	nortriptyline/ fluphenazine	dropouts	quality rating: 20
Solis 1970	Double blind RCT Active treatment: 8 weeks	Inclusion criteria: depression Age: not clear Country: Mexico Setting: in and outpatients	doxepin	responders dropouts	quality rating: 15
Staner 1995	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: RDC major depression, HMD 18+ Age: 18-65 Country: Belgium Setting: inpatients	paroxetine	responders mean score at end point dropouts	quality rating: 20
Stier 1982	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: Feighner criteria of primary depressive disorder Age: 24-60 Country: Israel Setting: in and outpatients	maprotiline	responders mean score at end point dropouts	quality rating: 16
Stott 1993	Double blind RCT Active treatment: 8 weeks	Inclusion criteria: patients with depression and anxiety, MADRS 16+, CAS 11+ Age: 18 - 65 Country: UK Setting: family practice	paroxetine	mean score at end point dropouts	quality rating: 20
Straker 1966	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: neurotic or psychotic depression Age: 27 average (males); 41 average (females) Country: Canada Setting: outpatients	imipramine and protryptiline	responders dropouts	quality rating: 18
Stuppaeck 1994	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM III major depression, melancholic subtype, HMD 18+ Age: 18-65 Country: Austria, Germany Setting: inpatients	paroxetine	responders mean score at end point dropouts	quality rating: 21
Toru 1972	Double blind RCT Active treatment: 3 weeks	Inclusion criteria: patients suffering from depression Age: 43 average Country: Japan Setting: in and outpatient	doxepin	responders dropouts	quality rating: 14
Trappe 1973	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: patients with depression Age: 34 average Country: Finland Setting: outpatents	doxepin/ chlordiazepoxide	dropouts	quality rating: 15
Upward 1988	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: patients with depressive illness Age: 24-63 Country: UK Setting: outpatients	fluoxetine	dropouts	quality rating: 18
Van Amerongen 1979	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: depressive state requiring antidepressants Age: 24 - 79 Country: France Setting: outpatients	amineptine	responders mean score at end point dropouts	quality rating: 19
Veith 1983	RCT, double-blind (not clear) Active treatment: 3 weeks	Inclusion criteria: Feighner criteria of primary unipolar affective disorder, Zung SDS 54+ Age: 19 - 58 Country: US Setting: outpatients	desipramine	responders mean score at end point dropouts	quality rating: 17
Von Bauer 1969	Double blind RCT, allocation concealment may be inadequate Active treatment: 4 weeks	Inclusion criteria: patients with depression Age: 53 average Country: Austria Setting: inpatients	doxepin	responders dropouts	quality rating:
Waite 1986	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: Feighner criteria for major depression, HMD 16+ Age: 65+ Country: UK Setting: inpatients	dothiepin and mianserin	responders dropouts	quality rating: 25
Watanabe 1978	Double blind RCT Active treatment: 5 weeks	Inclusion criteria: involutional melancholia, reactive depression Age: 12-70 Country: Japan Setting: in and outpatients	maprotiline	responders dropouts	quality rating: 16
Weissman 1975	Double blind RCT Active treatment: 4 weeks	Inclusion criteria: patients with depression, Raskin 7+ Age: 21-65 Country: US Setting: outpatients	maprotiline	dropouts	quality rating: 20
Wilcox 1994	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: DSM III major depression, HMD 18+ Age: 18+ Country: US Setting: outpatients	mianserin	dropouts	quality rating: 23
Wright 1976	Double blind RCT Active treatment: 8 weeks	Inclusion criteria: patients with depression Age: 46 average Country: UK Setting: outpatients	lofepramine	dropouts	quality rating: 14
Young 1987	Double blind RCT Active treatment: 6 weeks	Inclusion criteria: RDC moderately to severe unipolar depression, HMD 18+ Age: 20-65 Country: UK Setting: outpatients	fluoxetine	mean score at end point dropouts	quality rating: 19
Ziegler 1977	RCT, not double-blind Active treatment: 6 weeks	Inclusion criteria: Feighner criteria of affective disorder, HMD 21+ Age: 18-60 Country: US Setting: outpatients	nortriptyline

Appendix 2 Randomised control included in the systematic review

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Dorman T. Clinical trial comparison of a sustained release form of amitriptyline with dothiepin. J Int Med Res 1980; 8: 286-292

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Gomez-Martinez I. Preliminary double blind clinical trial with a new antidepressive doxepin. Curr Ther Res 1968; 10: 116-118

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