Review ArticleSystematic Reviews

Efficacy and Acceptability of Pharmacological Treatments for Depressive Disorders in Primary Care: Systematic Review and Network Meta-Analysis

Klaus Linde, Levente Kriston, Gerta Rücker, Susanne Jamil, Isabelle Schumann, Karin Meissner, Kirsten Sigterman and Antonius Schneider
The Annals of Family Medicine January 2015, 13 (1) 69-79; DOI: https://doi.org/10.1370/afm.1687

Article Figures & Data

Figures

  • Figure 1
    Figure 1

    Study selection process.

  • Figure 2
    Figure 2

    Network for the main efficacy outcome response.

    Figures indicate the number of direct comparisons (lines without figure indicate 1 comparison)

    Hypericum = extract from Hypericum perforatum L.; NaSSA = noradrenergic and specific serotonergic antidepressive agent (mianserin, mirtazapine); NRI = noradrenaline reuptake inhibitor (reboxetine); rMAO-A = reversible inhibitor of monoaminoxidase A (moclobemide, minaprine); SARI = serotonin (5-HT2) antagonist and reuptake inhibitor (trazodone); SNRI = serotonin-noradrenaline reuptake inhibitor (venlafaxine); SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic and tetracyclic antidepressant.

Tables

  • Table 1

    Overview of Antidepressant Medications Tested in the Included Trials and in the Meta-Analysis

    Medication ClassTrial Groups/Arms and Specific Medication Tested
    TCA, tricyclic and tetracyclic antidepressants40 Separate groups in trials, after pooling of groups in studies with more than 1 TCA, 37 arms in analyses
     14 Amitriptyline (1 pooling of 2 groups with different dosages, 1 pooled with dothiepin)
     8 Imipramine (1 pooled with desipramine)
     8 Dothiepin/dosulepin (1 pooled with amitriptyline)
     3 Clomipramine
     1 Amineptine
     1 Desipramine (pooled with imipramine)
     1 Doxepin
     1 Lofepramine
     1 Maprotiline
     1 Tianeptine
     1 Individualized TCA
    SSRI, selective serotonin reuptake inhibitors38 Arms in total, 37 after pooling of 2 arms in a study with 2 SSRI 35 arms
     12 Paroxetine
     9 Fluoxetine
     5 Sertraline
     5 Citalopram (1 pooled with escitalopram)
     2 Fluvoxamine
     3 Escitalopram (1 pooled with citalopram)
     1 Individualized SSRI
    SNRI, serotonin-noradrenaline reuptake inhibitor6 Arms in total
     6 Venlafaxine
    NRI, noradrenaline reuptake inhibitor1 Arm in total
     1 Reboxetine
    SARI, serotonin (5-HT2) antagonists and reuptake inhibitor5 Arms in total
     5 Trazodone
    NaSSA, noradrenergic and specific serotonergic antidepressive agents9 Arms in total
     8 Mianserin (2 underdosing)
     1 Mirtazapine
    rMAO-A, reversible inhibitors of monoaminoxidase A8 Arms in total, 6 in analyses
     4 Moclobemide,
     4 Minaprine (2 pooling of different dosages)
    Hypericum, extracts from Hypericum perforatum L. (St. John’s wort)15 Arms in total, 14 after pooling of 2 arms testing different extracts in 1 study; 12 different extracts
  • Table 2

    Characteristics of Included Studies

    CharacteristicPublication Year 1996 (1971, 2012)
    Number of patients
     Total15,161
     Median (minimum, maximum)162 (21, 1,385)
    Diagnosis, No. (%)
     Major depression only38 (58)
     Mixed/unclear25 (38)
     Minor depression/dysthymia3 (5)
    Classification of depression, No. (%)
     Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition)15 (23)
     Diagnostic and Statistical Manual of Mental Disorders (Third Edition)24 (36)
     International Classification of Diseases, Tenth Revision6 (9)
     International Classification of Diseases, Ninth Revision4 (6)
     Research Diagnostic Criteria4 (6)
     Not reported/other13 (20)
    Restricted to patients >55 y, No. (%)8 (12)
    Median length of treatment in weeks (minimum, maximum)6 (4, 52)
    Overall risk of bias, No. (%)
     High (high risk in 1 or more items)32 (49)
     Unclear (no item high risk, <3 low risk)23 (35)
     Low (at least 3 low, no high risk)11 (17)
    Data available for meta-analysis, No. (%)
     Response59 (89)
     Remission55 (83)
     Total number of patients dropping out60 (91)
     Number of patients dropping out due to adverse effects58 (88)
     Number of patients reporting adverse effects40 (61)
  • Table 3

    Results of Conventional and Network Meta-Analyses for the Main Efficacy Outcome Response

    MedicationTCASSRISNRINRILow-Dose SARINaSSArMAO-AHypericumPlacebo
    TCA
     OR (95% CI)a0.95 (0.84–1.08)0.83 (0.37–1.89)na1.43 (0.60–3.42)3.83 (1.67–8.75)1.65 (1.16–2.34)0.87 (0.54–1.41)1.67 (1.24–2.25)
     No. of studies; I2, %; P valueb18; 0; .45;2; 55; 0.14na2; 79; .0313; 0; .79;2; 24; 0.25;8; 25; .23;
     OR (95% CI)c1.04 (0.88–1.21)1.00 (0.71–1.40)1.23 (0.73–2.14)0.97 (0.65–1.47)1.55 (1.11–2.18)1.65 (1.10–2.45)0.86 (0.67–1.10)1.75 (1.42–2.15)
    SSRI
     OR (95% CI)a1.05 (0.93–1.19)0.92 (0.67–1.25)1.18 (0.85–1.65)na1.05 (0.54–2.03)na0.88 (0.63–1.23)1.57 (1.31–1.89)
     No. of studies; I2, %; P valueb18; 0; .454; 64; .041na3; 60; .08na6; 46; .107; 0; .83
     OR (95% CI)c0.97 (0.82–1.13)0.96 (0.71–1.29)1.19 (0.71–2.04)0.94 (0.63–1.43)1.50 (1.06–2.11)1.60 (1.03–2.54)0.83 (0.66–1.04)1.69 (1.40–2.04)
    SNRI
     OR (95% CI)a1.20 (0.53–2.72)1.09 (0.79–1.49)nanananana1.94 (0.96–3.93)
     No. of studies; I2, %; P valueb2; 55; .144; 64; .04nanananana1
     OR (95% CI)c1.00 (0.72–1.41)1.03 (0.77–1.42)1.23 (0.67–2.28)0.97 (0.60–1.63)1.55 (1.02–2.45)1.65 (0.98–2,80)0.86 (0.59–1.24)1.75 (1.24–2.47)
    NRI
     OR (95% CI)ana0.84 (0.61–1.18)nananananana
     No. of studies; I2, %; P valuebna1nananananana
     OR (95% CI)c0.60 (0.41–0.91)0.63 (0.41–0.87)0.61 (0.36–1.02)0.79 (0.41–1.57)0.94 (0.58–1.54)1.34 (0.66–2.70)0.52 (0.32–0.84)1.42 (0.81–2.49)
    Low-dose SARI
     OR (95% CI)a0.70 (0.29–1.67)nanana2.11 (1.37–3.25)nanana
     No. of studies; I2, %; P valueb2; 79; .03nanana4; 0; .56nanana
     OR (95% CI)c1.03 (0.68–1.55)1.06 (0.70–1.58)1.03 (0.61–1.67)1.26 (0.63–2.47)1.60 (1.07–2.42)1.70 (0.96–2.89)0.89 (0.58–1.38)1.80 (1.17–2.76)
    NaSSA
     OR (95% CI)a0.26 (0.11–0.60)0.95 (0.49–1.85)nana0.47 (0.31–0.73)1.07 (0.49–2.34)na1.34 (0.85–2.10)
     No. of studies; I2, %; P valueb13; 60; .08nana4; 0; .561na2; 0; .98
     OR (95% CI)c0.64 (0.46–0.93)0.67 (0.47–0.95)0.64 (0.41–0.98)0.79 (0.42–1.45)0.63 (0.41–0.93)1.06 (0.65–1.72)0.55 (0.37–0.82)1.13 (0.78–1.62)
    rMAO-A
     OR (95% CI)a0.61 (0.43–0.86)nananana0.93 (0.43–2.03)nana
     No. of studies; I2, %; P valueb3; 0; .79nananana1nana
     OR (95% CI)c0.61 (0.41–0.91)0.63 (0.41–0.97)0.61 (0.36–1.02)0.74 (0.37–1.52)0.59 (0.35–1.04)0.94 (0.58–1.54)0.52 (0.32–0.84)1.06 (0.67–1.66)
    Hypericum
     OR (95% CI)a1.15 (0.71–1.85)1.14 (0.81–1.59)nanananana2.02 (1.41–2.88)
     No. of studies; I2, %; P valueb2; 24; .256; 43; .12nanananana9; 43; .08
     OR (95% CI)c1.16 (0.81–1.50)1.20 (0.96–1.51)1.16 (0.80–1.68)1.43 (0.81–2.64)1.13 (0.72–1.73)1.80 (1.21. 2.67)1.92 (1.20–3.16)2.03 (1.63–2.53)

    • CI = confidence interval; CI = credible interval; hypericum = extract from Hypericum perforatum L.; rMAO-A = reversible inhibitor of monoaminoxidase A (moclobemide, minaprine); na = not available; NaSSA = noradrenergic and specific serotonergic antidepressive agent (mianserin, mirtazapine); NRI = noradrenaline reuptake inhibitor (reboxetine); OR = odds ratio; SARI = serotonin (5-HT2) antagonist and reuptake inhibitor (trazodone); SNRI = serotonin-noradrenaline reuptake inhibitor (venlafaxine); SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic and tetracyclic antidepressant.

      Note: Odds ratios >1 indicate more study discontinuation in patients receiving the treatment given in the row heading.

    • ↵a Conventional meta-analysis of within-study comparisons with pooled odds ratios.

    • ↵b Studies with direct comparisons available, with I2 value and P value from the χ2 test for heterogeneity.

    • ↵c From network meta-analysis.

  • Table 4

    Results of Conventional and Network Meta-Analyses for the Main Acceptability Outcome Study Discontinuation Because of Adverse Effects

    MedicationTCASSRISNRINRILow-Dose SARINaSSArMAO-AHypericumPlacebo
    TCA
     OR (95% CI)a1.15 (0.85–1.55)0.86 (0.46–1.62)na1.18 (0.46–3.01)0.51 (0.18–1.42)2.57 (1.18–5.60)2.33 (.92–5.93)2.30(1.10–4.81)
     No. of studies; I2, %; P value114; 43; .052; 0; .80na2; 54; .1415; 47; .112; 0; .897; 24; .25
     OR (95% CI)c1.12 (0.84–1.47)0.89 (0.55–1.37)0.44 (0.18–1.06)1.86 (0.92–3.75)0.64 (0.36–1.14)2.63 (1.49–5.09)2.37 (1.28–4.49)2.47 (1.59–3.84)
    SSRI
     OR (95% CI)a0.87 (0.64–1.17)0.81 (0.58–1.13)0.39 (0.28–0.55)na0.78 (0.42–1.44)na1.48 (0.77–2.85)1.86 (1.16–2.98)
     No. of studies; I2, %; P value114; 43; .054; 38; .181na3; 31; .23na6; 0; .928; 0; .64
     OR (95% CI)c0.89 (0.68–1.19)0.79 (0.55–1.19)0.39 (0.16–0.90)1.65 (0.85–3.45)0.57 (0.33–0.96)2.34 (1.24–4.84)2.11 (1.18–4.14)2.20(1.44–3.36)
    SNRI
     OR (95% CI)a1.16 (0.62–2.20)1.24 (0.89–1.74)nanananana2.96 (0.90–9.73)
     No. of studies; I2, %; P value12; 0; .804; 38; .18nanananana1
     OR (95% CI)c1.12 (0.73–1.81)1.26 (0.84–1.83)0.50 (0.19–1.23)2.08 (0.95–4.85)0.72 (0.36–1.37)2.95 (1.41–6.69)2.66 (1.33–5.57)2.77 (1.58–4.87)
    NRI
     OR (95% CI)a2.53 (1.81–3.53)nananananana
     No. of studies; I2, %; P value11nananananana
     OR (95% CI)c2.25 (0.95–5.48)2.54 (1.11–6.37)2.01 (0.82–5.20)4.19 (1.59–12.48)1.45 (0.58–3.74)5.94 (2.09–17.13)5.35 (1.99–14.94)5.58 (2.28–13.66)
    SARI
     OR (95% CI)a0.84 (0.33–2.15)nanana0.28 (0.10–0.79)nanana
     No. of studies; I2, %; P value12; 54; .14nanana3; 58; 0.09nanana
     OR (95% CI)c0.54 (0.26–1.08)0.61 (0.29–1.17)0.48 (0.21–1.05)0.24 (0.08–0.63)0.35 (0.16–0.64)1.42 (0.58–3.55)0.78 (0.31–1.83)1.33 (0.61–2.89)
    NaSSA
     OR (95% CI)a1.97 (0.71–5.51)1.28 (0.69–2.36)nana3.55 (1.27–9.90)nana3.52 (1.40–8.84)
     No. of studies; I2, %; P value113; 31; .23nana3; 58; .09nana2; 0; .90
     OR (95% CI)c1.56 (0.88–2.76)1.75 (1.04–3.02)1.39(0.73, 2.76)0.69 (0.27–1.71)2.89 (1.56–6.18)4.10(1.81–10.38)3.69 (1.71–8.56)3.85 (2.05–7.25)
    rMAO-A
     OR (95% CI)a0.39 (0.18–0.85)nanananananana
     No. of studies; I2, %; P value15; 47; .11nanananananana
     OR (95% CI)c0.38 (0.20–0.67)0.43 (0.21–0.81)0.34 (0.15–0.71)0.17 (0.06–0.48)0.71 (0.28–1.73)0.24 (0.10–0.55)0.90 (0.35–2.04)0.94 (0.43–2.05)
    Hypericum
     OR (95% CI)a0.43 (0.17–1.09)0.68 (0.35–1.30)nanananana0.79 (0.31–1.97)
     No. of studies; I2, %; P value12; 0; 0.896; 0; .92nanananana5; 0; .48
     OR (95% CI)c0.42 (0.22–0.78)0.47 (0.24–0.85)0.38 (0.18–0.75)0.19 (0.07–0.50)0.78 (0.31–1.83)0.27 (0.11–0.58)1.11 (0.49–2.83)1.04 (0.53–2.06)

    • CI = confidence interval; CI = credible interval; hypericum = extract from Hypericum perforatum L.; rMAO-A = reversible inhibitor of monoaminoxidase A (moclobemide, minaprine); na = not available; NaSSA = noradrenergic and specific serotonergic antidepressive agent (mianserin, mirtazapine); NRI = noradrenaline reuptake inhibitor (reboxetine); OR = odds ratio; SARI = serotonin (5-HT2) antagonist and reuptake inhibitor (trazodone); SNRI = serotonin-noradrenaline reuptake inhibitor (venlafaxine); SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic and tetracyclic antidepressant.

      Note: Odds ratios >1 indicate more study discontinuation in patients receiving the treatment given in the row heading.

    • ↵a Conventional meta-analysis of within-study comparisons with pooled odds ratios.

    • b Studies with direct comparisons available, with I2 value and P value from the χ2 test for heterogeneity.

    • ↵c From network meta-analysis.

Additional Files

  • The Article in Brief

    Efficacy and Acceptability of Pharmacological Treatments for Depressive Disorders in Primary Care: Systematic Review and Network Meta-Analysis

    Klaus Linde , and colleagues

    Background Most cases of depression are seen and managed in primary care, however, most research on depression treatment involves specialty settings. Antidepresssant drugs are an important element of depression treatment, but there is ongoing debate about whether their relatively small effects over placebo are clinically relevant. This study analyzes existing randomized trials of pharmacological treatments of depression in primary care to investigate whether antidepressants are more effective than placebo and whether there are differences in efficacy and acceptability between different types of depression medications.

    What This Study Found Antidepressants have short-term effects over placebo in primary care. SSRI (selective serotonin reuptake inhibitors) and TCA (tetracyclic antidepressants) have a somewhat more solid evidence base than other substance classes (with SSRI having a slightly better acceptability profile). Other pharmaceuticals (Hypericum, MAO-A, SNRI, NRI, NaSSa, SARI) showed some positive results, but due to limitations of the currently available evidence, a clear recommendation on their place in clinical practice remains difficult.

    Implications

    • The authors call for future research prioritizing large, long-term trials and observational studies addressing clinically relevant questions, such as the best management of mild-to-moderate depression and comparison of pharmacological and psychological treatments under conditions of routine care and stepped-care strategies.

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