Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea...

43
Antidepressants for depression Andrea Cipriani Psychiatry for General Practitioners Study Day – March 12 th 2019

Transcript of Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea...

Page 1: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

Antidepressants for depression

Andrea Cipriani

Psychiatry for General Practitioners Study Day – March 12th 2019

Page 2: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

Conflict of interest: none

Page 3: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict
Page 4: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict
Page 5: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

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.

Page 6: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict
Page 7: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

Group 1 of RCTs Group 2 of RCTs

Placebo Treatment B

DIRECT COMPARISON DIRECT COMPARISON

Treatment A Treatment A

Page 8: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

RCT 1 RCT 2

Placebo Treatment B

DIRECT COMPARISON DIRECT COMPARISON

“in common”

Treatment A Treatment A

Page 9: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

RCT 1 RCT 2

Placebo Treatment B

DIRECT COMPARISON DIRECT COMPARISON

“in common”

INDIRECT COMPARISON

Treatment A Treatment A

Page 10: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

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.

Page 11: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

Network of experimental comparisons

Page 12: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

Network of experimental comparisons

Page 13: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

Network of experimental comparisons

Page 14: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

Network of experimental comparisons

Page 15: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

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

Page 16: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict
Page 17: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

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

Page 18: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

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”

Page 19: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

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

Page 20: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

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”.

Page 21: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict
Page 22: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict
Page 23: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict
Page 24: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict
Page 25: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict
Page 26: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict
Page 27: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict
Page 28: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

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).

Page 29: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict
Page 30: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

Placebo

Drug A (low dose)

Drug A (high dose)

Drug B

Page 31: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

Diff.=5

Placebo

Drug A (low dose)

Drug A (high dose)

Drug B

Page 32: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

X

Placebo

Drug A (low dose)

Drug A (high dose)

Drug B

Page 33: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

X

LOCF

Placebo

Drug A (low dose)

Drug A (high dose)

Drug B

Page 34: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

Diff.=1

Diff.=5

LOCF

Placebo

Drug A (low dose)

Drug A (high dose)

Drug B

Page 35: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict
Page 36: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

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

Page 37: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

Can we personalise treatment in depression?

Page 38: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

0

0.2

0.4

0.6

0.8

1

1

ESCI

FLUOVENL

SERT AGOM

Cardiac risk

Insomnia

Sedation

Tremor

Weight gain

Nausea

- +

DIFFERENT PREFERENCES, DIFFERENT TREATMENTS

N

I

C

K

Page 39: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

0

0.2

0.4

0.6

0.8

1

1

0

0.2

0.4

0.6

0.8

1

1

MIRTPARO

SERT

AGOMVORT

ESCI

FLUOVENL

SERT AGOM

Cardiac risk

Insomnia

Sedation

Tremor

Weight gain

Nausea

- +

Cardiac risk

Insomnia

Sedation

Tremor

Weight gain

Nausea

- +

DIFFERENT PREFERENCES, DIFFERENT TREATMENTS

S

T

E

V

E

N

I

C

K

Page 40: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict
Page 41: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict
Page 42: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict
Page 43: Andrea Cipriani - TVSCNtvscn.nhs.uk/.../uploads/2019/03/5.-Andrea-Cipriani.pdf2019/03/05  · Andrea Cipriani Psychiatry for General Practitioners Study Day –March 12th 2019 Conflict

Thanks!

[email protected]

@And_Cipriani