Download Antidepressivi e depressione, tra medicina di base e servizi di salute

Dipartimento di Medicina e Sanità Pubblica
Sezione di Psichiatria e Psicologia Clinica
Università di Verona
Antidepressivi e depressione,
tra medicina di base e servizi di salute
mentale:
uno, nessuno o centomila?
Andrea Cipriani
Auditorium del Conservatorio – Matera, 7 novembre 2009
Quale ruolo hanno i farmaci antidepressivi nel trattamento
della depressione?
Qual è l'efficacia di tali farmaci:
• Grado di efficacia rispetto al placebo?
• Tollerabilità?
• Efficacia comparativa?
Uso nella pratica quotidiana:
• Setting diverso tra medicina generale e psichiatria (ad
es.,
appropriatezza della prescrizione nella
depressione
di minore
gravità)
• Uso spesso “non ottimale” (tempi di trattamento,
problema del dosaggio adeguato)
Depressive syndromes
Major
depression
Minor depression
Subthreshold depression
Adjustment disorder
Drug induced mood disorder
Nessuno?
The THREAD study (Kendrick et al., 2009)
• pragmatic, open label, multi-centre RCT comparing SSRIs plus supportive care
with supportive care alone for mild to moderate depression in primary care (no
placebo);
• 220 patients randomised (a score of at least 12 on the HDRS and for at least 8
weeks) outcomes rated by clinicians (HDRS) and patients (BDI) at 12 and 26
weeks.
• Supportive care: follow-up consultations 2, 4, 8 and 12 weeks after the baseline
assessment. GPs prescribed and, if thought necessary, switched SSRIs; GPs
discouraged to do so but could also prescribe antidepressants in the supportive
arm of the trial.
• In total, 87% of patients in the SSRIs plus supportive care arm and 20% in the
supportive care alone arm received SSRIs.
• Results: HDRS which showed a small (2.20 points) difference between the two
arms at 12 weeks (statistically significant); no significant difference was identified
on the BDI.
• Limitations: open label design, the lack of a placebo control, the overall small
effect size and the absence of effect on the patient-rated BDI, although it did
improve other patient-rated measures.
“… SSRIs could be of value in mild to moderate depression for people whose
symptoms have persisted for some time. However, given the small effect size this
study suggests that SSRIs should not be offered routinely in primary care for
people with mild to moderate depression, particularly when other treatments with
100%
42%
53%
100%
11%
Centomila
?
(NICE, 2007)
Uno?
RCT 1
Treatment A versus Placebo
RCT 2
Treatment B versus Placebo
DIRECT
COMPARISON
RCT 2
DIRECT
COMPARISON
RCT 1
Treatment A
Placebo
Treatment B
Placebo
DIRECT
COMPARISON
RCT 2
DIRECT
COMPARISON
RCT 1
Treatment A
Placebo
Placebo
“in common”
Treatment B
DIRECT
COMPARISON
RCT 2
DIRECT
COMPARISON
RCT 1
Treatment A
Placebo
Placebo
“in common”
INDIRECT
COMPARISON
Treatment B
DIRECT
COMPARISON
RCT 1
Treatment A
Treatment C
DIRECT
COMPARISON
RCT 2
Treatment B
Treatment C
DIRECT
COMPARISON
RCT 2
DIRECT
COMPARISON
RCT 1
Treatment A
Treatment C
Treatment C
“in common”
Treatment B
DIRECT
COMPARISON
RCT 2
DIRECT
COMPARISON
RCT 1
Treatment A
Treatment C
Treatment C
“in common”
INDIRECT
COMPARISON
Treatment B
3-study LOOP:
Study 1 (drug W vs drug F)
Study 2 (drug F vs drug L)
Study 3 (drug W vs drug L)
+
W
… is BETTER than …
…i
s be +
tter
than
…
F
L
+
n…
a
h
t
tter
e
b
… is
THE LOOP IS COHERENT
-
W
… is WORSE than …
…i
s be +
tter
than
…
F
… is
+
n…
a
h
t
er
bett
L
THE LOOP IS INCOHERENT !
We included only randomised controlled trials (RCTs) that compared any of the
following 12 new-generation antidepressants as monotherapy in the acute-phase
treatment of adults with unipolar major depression:
• bupropion
• citalopram
• duloxetine
• escitalopram
• fluoxetine
• fluvoxamine
• milnacipran
• mirtazapine
• paroxetine
• reboxetine
• sertraline
• venlafaxine
We excluded placebo groups where present and RCTs of women with postpartum depression.
Search strategy
To identify the relevant studies, we reviewed the Cochrane Collaboration
Depression, Anxiety, and Neurosis review group controlled trials registers
(CCDANDTR-studies and CCDANCTR-references) up to Nov 30, 2007.
These registers are compiled from systematic and regularly updated searches of
Cochrane Collaboration CENTRAL register,* AMED, CINAHL, EMBASE, LiLACS,
MEDLINE, UK National Research Register, PSYCINFO, PSYNDEX, supplemented
with hand searching of 12 conference proceedings
(http://www.thecochranelibrary.com).
•The Cochrane Central Register of Controlled Trials (CENTRAL) serves as the most
comprehensive source of reports of controlled trials. CENTRAL is published as part of The
Cochrane Library and is updated quarterly. As of January 2008 (Issue 1, 2008), CENTRAL
contains nearly 530,000 citations to reports of trials and other studies potentially eligible for
inclusion in Cochrane reviews, of which 310,000 trial reports are from MEDLINE, 50,000
additional trial reports are from EMBASE and the remaining 170,000 are from other sources
such as other databases and hand-searching.
Many of the records in CENTRAL have been identified through systematic searches of
MEDLINE and EMBASE. CENTRAL, however, includes citations to reports of controlled trials
that are not indexed in MEDLINE, EMBASE or other bibliographic databases; citations
published in many languages; and citations that are available only in conference proceedings
or other sources that are difficult to access. It also includes records from trials registers and
trials results registers (full details available at http://www.cochrane-handbook.org/).
Websites of pharmaceutical companies
• Eli Lilly: www.lilly.com
• Lundbeck: www.lundbeck.com
• Organon: www.organon.com
• Solvay: www.solvay.com
• Pfizer: www.pfizer.com
• GlaxoSmithKline: www.gsk.com
• Bristol Myers Squibb: www.bms.com
• Pierre Fabre : www.pierre-fabre.com
• Wyeth: www.wyeth.com
Medical Control Agencies
• Food and Drug Administration (USA): www.fda.gov
• European Medicines Agency (EU): www.emea.europa.eu
• Pharmaceuticals and Medical Devices Agency (Japan):
www.pmda.go.jp
• Therapeutic Goods Administration (Australia): www.tga.gov.au
117 RCTs
• 15 unpublished
25 928 individuals
• 24 595 (111 RCTs) EFF
• 24 693 (112) ACC
• 64% women
8.1 weeks (follow up)
109.8 (9–357) (sample)
23 3-arm RCTs (placebo)
7 3-arm RCTs (multi-dose)
The cumulative probabilities of being among the four most efficacious treatments
Efficacy
Rank
Drug
%
1.
Mirtazapine
24·4
2.
Escitalopram
23·7
3.
Venlafaxine
22·3
4.
Sertraline
20·3
5.
Citalopram
3·4
6.
Milnacipran
2·7
7.
Bupropion
2·0
8.
Duloxetine
0·9
9.
Fluvoxamine
0·7
10.
Paroxetine
0·1
11.
Fluoxetine
0·0
12.
Reboxetine
0·0
The cumulative probabilities of being among the four most efficacious treatments
and among the four best treatments in terms of acceptability
Efficacy
Rank
Drug
Acceptability
%
Drug
%
1.
Mirtazapine
24·4
Escitalopram
27·6
2.
Escitalopram
23·7
Sertraline
21·3
3.
Venlafaxine
22·3
Bupropion
19·3
4.
Sertraline
20·3
Citalopram
18·7
5.
Citalopram
3·4
Milnacipran
7·1
6.
Milnacipran
2·7
Mirtazapine
4·4
7.
Bupropion
2·0
Fluoxetine
3·4
8.
Duloxetine
0·9
Venlafaxine
0·9
9.
Fluvoxamine
0·7
Duloxetine
0·7
10.
Paroxetine
0·1
Fluvoxamine
0·4
11.
Fluoxetine
0·0
Paroxetine
0·2
12.
Reboxetine
0·0
Reboxetine
0·1
Meta-regression
In a meta-regression analysis to assess potential sponsorship bias, ORs and final
rankings did not substantially change. The cumulative probability of being among
the four best treatments became slightly smaller for those drugs in trials which
were sponsored by the marketing company, with the comparators moving up the
ranking slightly.
SPONSORSHIP
Efficacy
Rank
Drug
%
N of RCTs sponsored
by drug manufacturer
(or unclear) [%]
Total N of RCTs
included in the
MTM
1.
Mirtazapine
24·4
13 [100%]
13
2.
23·7
16 [84.2%]
19
3.
Escitalopra
m
Venlafaxine
22·3
17 [60.7%]
28
4.
Sertraline
20·3
12 [44.4%]
27
Meta-regression
In a meta-regression analysis to assess potential sponsorship bias, ORs and final
rankings did not substantially change. The cumulative probability of being among
the four best treatments became slightly smaller for those drugs in trials which
were sponsored by the marketing company, with the comparators moving up the
ranking slightly.
SPONSORSHIP
Efficacy
Acceptabilit
y
Rank
Drug
%
N of RCTs sponsored
by drug manufacturer
(or unclear) [%]
Total N of RCTs
included in the
MTM
1.
Mirtazapine
24·4
13 [100%]
13
2.
23·7
16 [84.2%]
19
3.
Escitalopra
m
Venlafaxine
22·3
17 [60.7%]
28
4.
Sertraline
20·3
12 [44.4%]
27
1.
24·4
16 [84.2%]
19
2.
Escitalopra
m
Sertraline
23·7
12 [44.4%]
27
3.
Bupropion
22·3
13 [92.8%]
14
4.
Citalopram
20·3
11 [68.7%]
(5 RCTs are CIT vs
ESC)
16
Conclusions
There is an evidence-based hierarchy among new-generation antidepressants
In terms of response, mirtazapine, escitalopram, venlafaxine, and sertraline were
more efficacious than duloxetine, fluoxetine, fluvoxamine, paroxetine, and
reboxetine. In terms of acceptability, escitalopram, sertraline, citalopram, and
bupropion were better tolerated than other new-generation antidepressants. These
results indicate that two of the most efficacious treatments might not be the best
for overall acceptability.
The most important clinical implication of the results is that ESC and SER might be
the best choice when starting a treatment for moderate to severe major depression
because they have the best possible balance between efficacy and acceptability.
We did not do a formal cost-effectiveness analysis; however, because some new
antidepressants are now off patent and available in generic form, their acquisition
cost is reduced (only two of the 12 antidepressants - escitalopram and duloxetine are still on patent in the USA and in Europe). Sertraline seems to be better than
escitalopram because of its lower cost in most countries. However, in the absence
of a full economic model, this recommendation cannot be made unequivocally
because several other costs are associated with the use of antidepressants (Le
Lay et al., 2006).
Reboxetine, fluvoxamine, paroxetine, and duloxetine were the least efficacious and
acceptable drugs, making them less favourable options when prescribing an acute
treatment for major depression. Reboxetine should not be used as a routine first-
Limitations
Acute phase only
Findings from this analysis apply only to acute-phase treatment (8 weeks) of
depression. Clinicians need to know whether (and to what extent) treatments work
within a clinically reasonable period. Clinically, the assessment of efficacy after 6
weeks of treatment or after 16–24 weeks or more might lead to wide differences in
treatment outcome. In many systematic reviews, the ability to provide valid
estimates of treatment effect is limited because trials with different durations of
follow-up have been combined (Zimmermann et al., 2002).
Study quality
Most trials included in our analysis did not report adequate information about
randomisation and allocation concealment, and this might undermine the validity of
overall findings. Nonetheless, all studies on antidepressants included in this metaanalysis were very similar in terms of design and conduct, and the scant
information in terms of quality assessment could be more an issue of reporting in
the text than real defects in study design, as it has been commonly found in other
systematic reviews (Huwiler-Müntener et al., 2002).
Sponsorship bias
(the bias associated with the commercial interests of study sponsors)
Because most studies comparing the newest antidepressants (mirtazapine,
escitalopram, buproprion, and duloxetine) were done by the pharmaceutical
companies marketing these compounds, this might be a source of bias.
Some discrepancies existed between some of the results of the multiple-treatments
meta-analysis and those in the direct comparisons (escitalopram vs citalopram and
mirtazapine vs venlafaxine). These findings emphasise a potential advantage of this
analysis that incorporates indirect and direct comparisons, decreasing the risk for
possible sponsorship bias.
However, limitations of the primary trials and potential confounders (such as dose
issues) can affect the validity of the findings.
Readers cannot fully appreciate the meaning of a study without acknowledging the
biases in the design and interpretation that can arise when a sponsor might benefit
from a study publication. Such associations should be made clear to let anyone judge
the relevance of findings
Placebo-controlled trials?
This kind of trial are required by regulatory authorities both in the US and Europe to
adequately assess the efficacy of novel antidepressant drugs (Kupfer & Frank, 2002).
Placebo-controlled trials are mainly designed for regulatory approval purposes; to
meet both ethical and safety requirements, they tend to recruit patients with a mild
form of disease (Kirsch & Moncrieff). Moreover, the selective publication of placebocontrolled antidepressant trials and its effect on apparent efficacy has been shown
(Turner et al., 2008) and there is currently controversy on this topic (Kirsch et al.,
2008).
Placebo-controlled trials may be efficient because (need for smaller sample sizes),
however difficulties in carrying out these trials when effective treatments are known to
exist can introduce artifacts into clinical trials (Geddes & Cipriani, 2004). Response to
placebo across antidepressant trials has clearly increased in the past two decades,
with a similar increase occurring in the fraction of patients responding to active
medication as well (Walsch et al., 2002). The change in placebo response does not
seem to be directly explained by changes in study characteristics (inflation of baseline
severity?)
This study suggests that sertraline could be used as a standard comparator in phase
III and also in pragmatic trials to increase the real-world applicability of the results.
Furthermore, the need of new treatments to show either greater efficacy or
acceptability than an existing standard therapy would serve as a disincentive to the
development of me-too agents that offer little to patients other than increased costs.
August 2006 – December 2009
May 2009 – December 2012
Grazie!
[email protected]