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Antidepressants for depression
Andrea Cipriani
Psychiatry for General Practitioners Study Day – March 12th 2019
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Conflict of interest: none
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Ideally, clinicians would like to know how all the different options rank against each other and how big the differences are between all the available options.
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Group 1 of RCTs Group 2 of RCTs
Placebo Treatment B
DIRECT COMPARISON DIRECT COMPARISON
Treatment A Treatment A
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RCT 1 RCT 2
Placebo Treatment B
DIRECT COMPARISON DIRECT COMPARISON
“in common”
Treatment A Treatment A
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RCT 1 RCT 2
Placebo Treatment B
DIRECT COMPARISON DIRECT COMPARISON
“in common”
INDIRECT COMPARISON
Treatment A Treatment A
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This emerging review format is not popular yet because of important difficulties with the necessary statistical component - Multiple Treatments Meta-analysis or Network Meta-Analysis.
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Network of experimental comparisons
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Network of experimental comparisons
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Network of experimental comparisons
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Network of experimental comparisons
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Comparison of interventions which haven’t been
directly compared in any trial
Comprehensive use of all available data (direct
evidence + indirect evidence)
Improved precision for each comparison
Ranking of many treatments for the same
condition
Advantages of NMA
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Rationale
Antidepressants are widely used worldwide, however…• long-lasting debate about their efficacy • differences between individual drugs?
Focus
Acute treatment of adults with unipolar major depressive disorder
Aim
To compare:• all licensed second-generation ADs • 4 reference first-generation ADs • placebo
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Methods
• Only double-blind RCTs, published and/or unpublished
• Antidepressants (or placebo) as oral monotherapy
• Adults (≥18 years old) with a primary diagnosis of MDD (standard operationalised diagnostic criteria)
• Electronic databases searched until January 8th 2016.
• Manual searches of international trial registers, websites of regulatory agencies, pharmaceutical companies and key scientific journals in the field.
• Original studies’ authors contacted “systematically”
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1. Agomelatine2. Bupropion 3. Citalopram 4. Desvenlafaxine5. Duloxetine 6. Escitalopram 7. Fluoxetine 8. Fluvoxamine 9. Levomilnacipran10. Milnacipran11. Mirtazapine 12. Paroxetine 13. Reboxetine14. Sertraline 15. Venlafaxine 16. Vilazodone17. Vortioxetine18. Amitriptyline 19. Clomipramine 20. Trazodone 21. Nefazodone
Exclusion:
• Bipolar disorder• Psychotic or treatment-resistant
depression • Serious concomitant medical illness
[Only data within the therapeutic range]
Outcomes
• Response• All-cause dropout
• Secondary:• endpoint depression score• remission• Dropouts due to adverse events
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Statistical analysis
• Summary odds ratios (OR) for dichotomous outcomes and standardisedmean differences (SMD, Cohen’s d) for continuous outcomes using pairwise and network meta-analysis
• In network meta-analysis we assumed that the amount of heterogeneity was the same for all treatment comparisons
• The transitivity assumption was evaluated by comparing the distribution of clinical and methodological variables that could act as effect modifiers.
• We performed a statistical evaluation of consistency (i.e. the agreement between direct and indirect evidence) using the design-by treatment test and by separating direct from indirect evidence.
• Analysed data (independently) with OpenBUGS, STATA and R
• Used GRADE for “certainty of evidence”.
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Figure 2. Response rate in active arms versus dropout rate due to any cause.
Blue: arms with probability of receiving placebo π>0%. Black: arms with probability of
receiving placebo π=0%. The red line corresponds to the multivariate regression line
(exponentiated).
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Placebo
Drug A (low dose)
Drug A (high dose)
Drug B
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Diff.=5
Placebo
Drug A (low dose)
Drug A (high dose)
Drug B
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X
Placebo
Drug A (low dose)
Drug A (high dose)
Drug B
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X
LOCF
Placebo
Drug A (low dose)
Drug A (high dose)
Drug B
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Diff.=1
Diff.=5
LOCF
Placebo
Drug A (low dose)
Drug A (high dose)
Drug B
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Limitations
• Missing studies? (however, no evidence of publication bias)
• Quality of evidence
• No cost-effectiveness analysis
• Potentially important effect modifiers are missing
• Limited number of outcomes investigated (i.e. specific AEs or global functioning)
• Average treatment effects
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Can we personalise treatment in depression?
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Nausea
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DIFFERENT PREFERENCES, DIFFERENT TREATMENTS
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