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the bmj |
BMJ
2016;352:i65 | doi: 10.1136/bmj.i65
RESEARCH
1
open access
1Nordic Cochrane Centre,
Rigshospitalet, Copenhagen,
Denmark
2University of Copenhagen,
Faculty of Health and Medical
Sciences, Denmark
Correspondence to: T Shar ma
Nordic Cochrane Centre,
Rigshospitalet, Blegdamsvej 9,
Depar tment 7811, 2100 Ø
Copenhagen, Denmark
ts@cochrane.dk
Additio nal material is published
online onl y. To view plea se visit
the journal online (http://dx.doi.
org/10.1136/bmj.i65)
Cite this as: BMJ ;:i
http://dx.doi.org/10.1136/bmj.i65
Accepted: 03 December 2015
Suicidality and aggression during antidepressant treatment:
systematic review and meta-analyses based on clinical
studyreports
Tarang Sharma,1 ,2 Louise Schow Guski,1 ,2 Nanna Freund,1 ,2 Peter C Gøtzsche1 ,2
ABSTRACT
OBJECTIVE
To study serious harms associated with selective serotonin
and serotonin-norepinephrine reuptake inhibitors.
DESIGN
Systematic review and meta-analysis.
MAIN OUTCOME MEASURES
Mortality and suicidality. Secondary outcomes were
aggressive behaviour and akathisia.
DATA SOURCES
Clinical study reports for duloxetine, fluoxetine,
paroxetine, sertraline, and venlafaxine obtained from
the European and UK drug regulators, and summary
trial reports for duloxetine and fluoxetine from Eli
Lilly’s website.
ELIGIBILITY CRITERIA FOR STUDY SELECTION
Double blind placebo controlled trials that contained
any patient narratives or individual patient listings of
harms.
DATA EXTRACTION AND ANALYSIS
Two researchers extracted data independently; the
outcomes were meta-analysed by Peto’s exact method
(xed eect model).
RESULTS
We included 70 trials (64 381 pages of clinical study
reports) with 18 526 patients. These trials had
limitations in the study design and discrepancies in
reporting, which may have led to serious under-
reporting of harms. For example, some outcomes
appeared only in individual patient listings in
appendices, which we had for only 32 trials, and we did
not have case report forms for any of the trials.
Dierences in mortality (all deaths were in adults, odds
ratio 1.28, 95% condence interval 0.40 to 4.06),
suicidality (1.21, 0.84 to 1.74), and akathisia (2.04, 0.93
to 4.48) were not signicant, whereas patients taking
antidepressants displayed more aggressive behaviour
(1.93, 1.26 to 2.95). For adults, the odds ratios were
0.81 (0.51 to 1.28) for suicidality, 1.09 (0.55 to 2.14) for
aggression, and 2.00 (0.79 to 5.04) for akathisia. The
corresponding values for children and adolescents
were 2.39 (1.31 to 4.33), 2.79 (1.62 to 4.81), and 2.15
(0.48 to 9.65). In the summary trial reports on Eli Lilly’s
website, almost all deaths were noted, but all suicidal
ideation events were missing, and the information on
the remaining outcomes was incomplete.
CONCLUSIONS
Because of the shortcomings identied and having
only partial access to appendices with no access to
case report forms, the harms could not be estimated
accurately. In adults there was no signicant increase
in all four outcomes, but in children and adolescents
the risk of suicidality and aggression doubled. To
elucidate the harms reliably, access to anonymised
individual patient data is needed.
Introduction
Selective serotonin reuptake inhibitors (SSRIs) and
serotonin-norepinephrine reuptake inhibitors (SNRIs)
are some of the most commonly prescribed drugs.1 2
SSRI induced suicidality was first reported in 19903 but
only became generally recognised after a BBC Pan-
orama programme focused on it in 2002.4
A 2004 UK review showed a noticeable discrepancy
between published and unpublished trials and
increased suicidal behaviour in children and adoles-
cents (aged <18 years),5 which resulted in serious warn-
ings against these drugs being used in this age group.6
It is widely believed that the risk of suicide is not
increased in adults, and support for this was provided
by a Food and Drug Administration meta-analysis of
about 100 000 patients.7 However, a large systematic
review of published trials found an increase in suicide
attempts with SSRI treatment,1 and another review
using data submitted to the UK’s Medicines and Health-
care products Regulatory Agency (MHRA) could not
rule out an increased risk of suicidal behaviour during
early treatment with these drugs.8
For aggressive behaviour (for example, hostility,
assault) in general, reports are conflicting.9-15 A UK
review using MHRA data found an increase in hostility
in children and adolescents,16 and an analysis of
adverse events reported to the FDA showed that antide-
pressants were disproportionately involved in cases of
violence, including murder.17 Many cases of aggressive
behaviour have been reported,2 4 but, unlike with
WHAT IS ALREADY KNOWN ON THIS TOPIC
Important information on harms is oen missing in published trial reports
Clinical study reports should therefore be the preferred source for systematic
reviews of drugs
Antidepressants can increase the risk of suicide in children and adolescents
WHAT THIS STUDY ADDS
Despite all the limitations we identied in the trials and in the clinical study reports,
we found an increase in events of aggression with antidepressants (lost in adults
alone), with a doubling of both suicidality and aggression in children and adolescents
Selective reporting of relevant harms across the dierent sections of the clinical study
reports meant that patient narratives, tables with individual patient listings (oen
found in appendices), and case report forms are needed for complete information
Online summary reports of trials available from Eli Lilly’s website are inadequate as
source documents for identifying harms data
doi: 10.1136/bmj.i65 |
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2016;352:i65 | the bmj
RESEARCH
2
suicidality, little systematic research has been under-
taken. Perpetrators of school shootings and similar
events have often been reported to be users of antide-
pressants18 and the courts have in many cases found
them not guilty as a result of drug induced insanity.4
Akathisia is an extreme form of restlessness, which
some patients describe as wanting to “jump out of their
skin,” that may increase the risk of suicide and vio-
lence.2 4 11 19-25 The Diagnostic and Statistical Manual of
Mental Disorders describes akathisia or similar activa-
tion symptoms as “medication-induced movement dis-
order not otherwise specified.”26
Clinical study reports are detailed summaries of trial
results prepared by the drug industry for submission to
regulatory authorities to obtain authorisation for market-
ing. A recent review of clinical study reports showed that
essential information on patient relevant outcomes was
often missing in the published articles.27 Research
undertaken by our centre using nine clinical study
reports on duloxetine found that data on major harms
was missing from journal articles and in summary trial
reports.28 We did not have access to any case report forms
(paper or electronic questionnaires that contain the col-
lected data on each participant in the trial), although
they would have been the ideal information source.28
We report here our results for mortality, suicidality,
aggression, and akathisia based on clinical study
reports for five dierent antidepressants.
Methods
In 2011, we requested clinical study reports on SSRIs
and SNRIs from the European Medicines Agency and
the UK’s MHRA. We did not get access to clinical
study reports for all trials or for all the commonly pre-
scribed drugs, and we did not receive case report
forms for any of the trials. One researcher (TS)
selected those clinical study reports that described
double blind placebo controlled trials and which
contained patient narratives (brief summaries of
deaths, serious adverse events, or other events of
clinical importance) or listings of adverse events in
individual patients (with details such as patient iden-
tifier, the adverse event (preferred term and verbatim
term), duration, severity, and outcome).28
We were able to include five drugs: duloxetine, fluox-
etine, paroxetine, sertraline, and venlafaxine (or venla-
faxine extended release). We converted the clinical
study reports to readable portable document format,
and one researcher (TS) copied all relevant pages—with
study information, protocols, all adverse event summa-
ries and tables, relevant appendices (where available),
patient narratives, and individual patient listings—for
use in data extraction.
As a pilot, we randomly chose one report for each
drug and read it in its entirety to help understand the
dierent formats of the clinical study reports and to
refine the data extraction form. We had planned that
the second observer would extract the data blindly,
with the treatment groups masked, but the pilot showed
that the format and language used made blinding
impossible. The primary researcher (TS) and a second
observer (LSJ or NF) extracted data from the selected
pages of all the clinical study reports independently;
disagreements were resolved by discussion and docu-
mented using κ statistics (see supplementary data A).
Outcomes
The primary outcomes were mortality and suicidality
(suicide, suicide attempt or preparatory behaviour,
intentional self harm, and suicidal ideation); secondary
outcomes were aggressive behaviour and akathisia. To
identify the primary outcomes, we used the same terms
and phrases as those of the FDA7 29 and added addi-
tional terms from our pilot. We searched the clinical
study reports both electronically and manually. For
people with more than one suicidality event, we
counted only the most severe one, whereas this was not
possible for the secondary outcomes, which only
allowed us to count events. Terms for aggressive
behaviour were informed by the pilot, and akathisia
was identified by searching for “akathisia” in the text
(see supplementary data A). All relevant events were
classified using the Medical Dictionary for Regulatory
Activities (MedDRA) coding dictionary. For duloxetine
and fluoxetine, we compared the data with the sum-
mary trial reports from Eli Lilly’s website.30
For meta-analysis of rare events, we reported odds
ratios using Peto’s exact method and calculated 95%
confidence intervals with a fixed eect model using
RevMan 5.3.31 32 All post-randomisation events were
included, so when data from the lead-out and post-treat-
ment phases were available, we combined them with the
data from the randomised phase. In trials with multiple
intervention arms, we added the data on arms arithmeti-
cally to get a combined drug arm. We planned and con-
ducted subgroup analyses for adults for all outcomes
and for suicides and suicide attempts combined, and
did post-hoc analyses for suicides and children and ado-
lescents and a sensitivity analysis removing data from
fraudulent centres, as suggested by peer reviewers.
Patient involvement
No patients were involved in setting the research ques-
tion or the outcome measures, nor were they involved in
the design and implementation of the study. We plan to
involve patient organisations in the dissemination of
our results.
Results
We excluded 125 of the 198 clinical study reports: 96
were not double blind placebo controlled trials, 28 were
studies in healthy volunteers, and one was a crossover
trial (fig 1). Of the remaining 73 clinical study reports,
we excluded five that had no patient narratives or indi-
vidual patient listings of adverse events. The 68
included clinical study reports amounted to 64 381
pages and corresponded to 70 trials.
Trial characteristics and study design
The experimental drugs were duloxetine (23 trials), flu-
oxetine (n=3), paroxetine (n=8), sertraline (n=28), and
venlafaxine (n=8). In total, 10 258 patients received a
the bmj |
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2016;352:i65 | doi: 10.1136/bmj.i65
RESEARCH
3
drug and 6832 a placebo. Fifteen trials had an additional
(SSRI or SNRI) comparator in 669 patients (228 receiving
fluoxetine and 441 receiving paroxetine) and a tricyclic
or tetracyclic comparator in 767 patients. Eleven of the
trials (12% of the patients) concerned children and ado-
lescents. Table 1 shows the indications for treatment; 34
trials included 7882 patients with major depressive dis-
order. Patients at risk of suicide were excluded in 44 tri-
als (63%); in 16 trials, suicide risk was not an exclusion
criterion (23%), whereas it was unknown in 10 trials
(14%). The randomised phase of the trials lasted from
one to 54 weeks (median nine weeks).
Sixty trials (86%) had a placebo lead-in period (4 to
14 days, median 7 days) and all of them excluded from
randomisation those who improved while receiving pla-
cebo, as judged by their Hamilton scores or similar.
Rarely was there any information about the numbers
excluded.
It was unclear to what extent sedatives were allowed
or used. Four duloxetine trials and four sertraline trials
allowed benzodiazepines or similar psychoactive drugs.
However, in at least 50 trials (71%, we did not have
access to the full protocol for all the trials), sedatives
such as choral hydrate or zolpidem were allowed if the
patients had diculty sleeping.
The quality of the clinical study reports varied. For 32
trials we had individual patient listings of adverse
events for all patients (in appendices, apart from the
venlafaxine trials where the listings were part of the
main report). We had access to the protocol for 44 trials;
for the remaining trials, only a summary of the study
design was available. It seemed that all other appendi-
ces were either only “available on request” to the author-
ities or came under “the system of exceptions set out in
the Regulation (EC) No 1049/2001,” and so could not be
released to us. This is in line with the guidance for clini-
cal study reports, where certain appendices are not
required to be submitted to the EMA.33 For 27 trials, we
only had abbreviated or summary clinical study reports;
some of these were titled accordingly whereas others
were called clinical study reports, although they were
only short summaries of about 100 pages. For four trials
of sertraline, we only had summary reports combining
two trials each (trials 51 and 52, and trials 53 and 54) for
which the protocols were the same. We analysed the
results accordingly. Key characteristics of the included
trials are available in the supplementary data B.
The drug companies had concerns about the validity
of the data or fraudulent behaviour in three trials. The
data from one centre in trial 28 was not included in the
ecacy analyses “due to concerns over the validity of
the data,” and in trial 34, one centre was shut down
“following an internal audit that detected significant
compliance violations.” Four centres in trial 70 exhib-
ited potentially fraudulent behaviour: three centres had
their study records “impounded by the Swiss police for
fraud”; and for the fourth centre, “Many of the enrolled
patients . . . had identical evaluations for consecutive
visits, and . . . all 35 patients from this site had very sim-
ilar evaluation patterns.”
The interobserver agreement for our assessments was
high (κ=0.94). Most disagreements resulted from errors
in data extraction; discussion and consensus was
needed for only two events.
Mortality
Sixteen deaths occurred, all in adults: one in the pla-
cebo lead-in phase and one in a 12 week lead-in phase
during treatment with duloxetine 60 mg/day. Post-ran-
domisation, nine deaths occurred during treatment
with an SSRI or SNRI and four with placebo (odds ratio
1.28, 95% confidence interval 0.40 to 4.06) plus one
with imipramine (table 2 , fig 2, and supplementary data
C). As none of the deaths occurred in fraudulent cen-
tres, no sensitivity analysis was needed.
Four deaths were misreported by the company, in
all cases favouring the active drug. One death in a
Clinical study reports available from regulators (n=198)
Total clinical study reports with double blind placebo controlled
and/or active comparator randomised controlled trials (n=73)
Total relevant randomised controlled trial clinical study reports
included, corresponding to 70 randomised controlled trials (n=68)
Excluded non-double blind randomised
controlled trials, healthy volunteer
studies, and crossover randomised
controlled trials (n=125)
Excluded trial reports without any individual
patient listings or narratives (n=5)
Fig | Flowchart showing selection of relevant studies for
inclusion
Table | Overview of indications in trials
Indication Drug s (No of trials)
Major depressive disorder Duloxetine (12), fluoxetine (2), paroxetine (3), sertraline
(9), venlafa xine or venlafa xine extended release (8)
Obsessive compulsive disorder Fluoxetine (1), paroxetine (1), ser traline (7)
Post-traumatic stress disorder Paroxetine (3), ser traline (4)
Stress urinary incontinence Duloxetine (8)
Panic disorder Sertraline (5)
Generalised so cial phobia or social anxiet y disorder or social phobia Sertraline (2), paroxetine (1)
Irritative symptoms of benig n prostatic hyperplasia Du loxe tine (1)
Diabetic peripheral neuropathic pain Du loxe tine (1)
Fibromyalgia Du loxe tine (1)
Non-insulin-dependent diabetes mellitus Sertraline (1)
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participant receiving paroxetine (trial 31) was called a
post-study event, taking place 21 days after the patient
had admitted to taking the last dose, but this was on
day 63 out of the 84 days of randomised treatment.
Moreover, the patient had detectable paroxetine in the
blood at the time of death. A patient receiving venlafax-
ine (trial 69) attempted suicide by strangulation with-
out forewarning and died five days later in hospital.
Although the suicide attempt occurred on day 21 out of
the 56 days of randomised treatment, the death was
called a post-study event as it occurred in hospital and
treatment had been discontinued because of the suicide
attempt. Conversely, a patient receiving placebo (trial
62) died on day 404, 26 days after the randomised phase
ended, but the death was not listed as a post-study
event as the patient had allegedly taken treatment until
the previous day. Finally, a death in a participant receiv-
ing venlafaxine (trial 70) that occurred three months
after treatment was only noted in the patient narratives
and nowhere else in the clinical study report.
Suicidality
Overall, 155 suicidality events took place, 13 before ran-
domisation. The odds ratio post-randomisation for sui-
cidality in patients was 1.21 (95% confidence interval
0.84 to 1.74) and was similar for number of suicidality
events (1.14, 0.80 to 1.64). The odds ratio for suicidality in
adults was 0.81 (0.51 to 1.28) and 0.77 (0.49 to 1.21 for
events) and for children and adolescents was 2.39 (1.31 to
4.33) and 2.24 (1.24 to 4.04 for events). None of the suicid-
ality events occurred in patients from fraudulent centres.
See table 3 , fig 3 and supplementary data C and D.
Suicides
Six suicides were reported, one in the duloxetine
lead-in phase. Post-randomisation five suicides were
reported: two in the study drug group, two in the pla-
cebo group (odds ratio 0.58, 95% confidence interval
0.07 to 4.48), and one in the imipramine group (see sup-
plementary data C and D).
Suicide attempts
We counted all attempted suicides, including intentional
self harm (for example, slitting of wrists), intentional
overdoses, and obvious preparatory events (for example,
putting a knife to the wrist or neck, but being stopped
before any harm). Six of the 73 events (n=70 patients) took
place before randomisation (four in participants taking
duloxetine and two in participants taking placebo).
One of the events, in a participant taking placebo
before randomisation, occurred on day 29, although the
lead-in phase was supposed to last only 14 days. Also,
one of the four suicide attempts in participants taking
duloxetine before randomisation was only identified by
Table | Number of all cause mortality events in included trials
Phase of trial
No of deaths
Before
randomisation Drug arm
Third ar m
(imipramine)
Placebo
arm
Before randomisation 2 0 0 0
Randomised phase 0 8 1 3
Lead-out and post-treatment 0 1 0 1
Total No of deaths 2 9 1 4
Drugs: duloxetine, fluoxetine, paroxetine, sertraline, venlafaxine.
Trial 03
Trial 08
Trial 16
Trial 23
Trial 30
Trial 31
Trial 62
Trial 69
Trial 70
Total (95% CI)
Test for heterogeneity:
χ2=5.40, df=8,
P=0.71, I
2=0%
Test for overall eect: z=0.41, P=0.68
0.99 (0.09 to 11.05)
4.55 (0.07 to 285.11)
7.52 (0.15 to 379.06)
0.65 (0.05 to 8.83)
0.14 (0.00 to 6.91)
0.14 (0.15 to 385.12)
0.13 (0.00 to 6.59)
4.47 (0.07 to 286.83)
3.97 (0.05 to 320.94)
1.28 (0.40 to 4.06)
23.0
7.8
8.7
19.6
8.7
8.7
8.7
7.7
6.9
100.0
0.01 0.1 010 100
Study
Increased
harm placebo
Increased
harm drugs
Peto odds ratio
xed (95% CI)
Peto odds ratio
xed (95% CI)
Weight
(%)
2/188
1/175
1/227
2/342
0/160
1/151
0/181
1/167
1/180
9/1771
Drugs
1/93
0/90
0/231
1/115
1/162
0/156
1/175
0/83
0/68
4/1173
Placebo
No of events/total
Fig | Meta-analysis of all cause mortality for selective serotonin reuptake inhibitors (SSRI s)
or serotonin-norepinephrine reuptake inhibitors (SNRI s) compared with placebo post-
randomisation
Table | Overall suicidality events in included trials, before and post-randomisation
Suicidality events Duloxetine Fluoxetine Paroxetine Sertraline Venla faxine All drugs Placebo Imipramine
Before randomisation
Drug event:
Suicides 1—* —* —* —* 1 0 —*
Suicide attempts 4—* —* —* —* 4 2 —*
Suicidal ideation 4—* —* —* —* 4 2 —*
Suicidality 9 9 4
Post-randomisation
Drug (any ar m) event:
Suicides 1 0 0 0 1 2 2 1
Suicide attempts 8 5 18 9 3 43 22 2
Suicidal ideation 8 1 18 11 341 25 4
Suicidality 17 636 20 7 86 in 85 patients 49 in 46 patients 7 in 7 patients
Total population 4277 456 1766 3165 12 63 10 9 27 6832 767
*No patients received these drugs pre-randomisation.
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2016;352:i65 | doi: 10.1136/bmj.i65
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going over the appendices containing individual patient
listings. This “possible suicide attempt” was listed as
“mild” and was not documented elsewhere in the clini-
cal study report and there was no patient narrative.
Five of the 67 post-randomisation events occurred
during the lead-out or post-treatment phase of the trials
(in three patients receiving study drugs and in two
receiving placebo).
Of the remaining 62 suicide attempts (in 59 patients),
40 occurred in 39 patients receiving the study drug, 20 in
18 patients receiving placebo, and two in two patients
receiving imipramine. Four of these events were only
listed in the individual patient listings and three others
only noted in adverse events tables (no further informa-
tion was available as there was no narrative). Twenty
seven events were coded as emotional lability or worsen-
ing depression, although in patient narratives or individ-
ual patient listings they were clearly suicide attempts.
Conversely, several cases of suicidal ideation were called
suicide attempts in the adverse events tables. One sui-
cide attempt (intentional overdose with paracetamol
(acetaminophen)) in a patient receiving fluoxetine was
described as “elevated liver enzymes” in the adverse
events tables, in contrast with the narrative (see supple-
mentary data C). There was no dierence between sui-
cides and suicide attempts (odds ratio 1.05, 95%
confidence interval 0.63 to 1.75). The odds ratio for adults
was 0.60 (0.29 to 1.24) and for children and adolescents
was 1.85 (0.90 to 3.83, see supplementary data D).
Suicidal ideation
Seventy five participants experienced 76 suicidal ideation
events, of which six events were in the lead-in phase (four
were taking duloxetine and two placebo). Two of the four
events in the duloxetine users were severe and had
patient narratives. A third event was mild and was only
recorded in treatment emergent adverse events tables.
The fourth event, mild suicidal thoughts, appeared only
in the appendix containing individual patient listings. Of
the 70 post-randomisation events, 41 occurred in partici-
pants receiving study drugs, 25 in those receiving placebo,
and four in those receiving imipramine.
Sixty two patients experienced 63 events during the
randomised phase of the trials (34 events in those
receiving drugs, 25 in 24 participants receiving placebo,
and four in participants receiving imipramine). Thirty
two of these events were coded as emotional lability or
worsening of depression in the treatment emergent
adverse events tables, but it was clear from the patient
narratives or individual patient listings that they were
in fact ideation events.
Seven events occurred in the lead-out or post-treat-
ment phases of the trials, and all in participants receiv-
ing the study drug (see supplementary data C).
Aggressive behaviour
Three events of aggressive behaviour in participants
receiving duloxetine and two in participants receiving pla-
cebo took place before randomisation. Post- randomisation
there were 62 events in participants receiving the study
drugs, 28 in participants receiving placebo, and four in
Adults
Trial 03
Trial 04
Trial 05
Trial 06
Trial 07
Trial 08
Trial 09
Trial 11
Trial 30
Trial 31
Trial 32
Trial 38
Trial 39
Trial 40
Trial 44
Trial 45
Trial 46
Trial 47
Trial 48
Trial 49
Trial 50
Trial 51 and 52
Trial 53 and 54
Trial 59
Trial 63
Trial 64
Trial 67
Trial 68
Trial 69
Trial 70
Subtotal (95% CI)
Test for heterogeneity:
χ2=35.60, df=29,
P=0.19, I
2=19%
Test for overall eect: z=0.91, P=0.36
Children and adolescents
Trial 24
Trial 25
Trial 26
Trial 27
Trial 28
Trial 29
Trial 33
Trial 34
Trial 42
Trial 43
Trial 56
Subtotal (95% CI)
Test for heterogeneity:
χ2=8.90, df=10,
P=0.54, I
2=0%
Test for overall eect: z=2.86, P=0.004
Total (95% CI)
Test for heterogeneity:
χ2=52.46, df=40,
P=0.09, I
2=24%
Test for overall eect: z=1.02, P=0.31
Test for subgroup dierences:
χ2=7.96,
df=1, P=0.005, I
2
=87.4%
0.46 (0.02 to 8.88)
4.50 (0.07 to 285.95)
7.45 (0.77 to 72.30)
0.39 (0.05 to 2.84)
7.72 (0.15 to 389.54)
3.84 (0.16 to 92.95)
3.82 (0.16 to 93.42)
1.13 (0.24 to 5.23)
0.51 (0.10 to 2.58)
7.64 (0.15 to 385.12)
1.48 (0.19 to 11.05)
0.42 (0.02 to 7.30)
0.13 (0.01 to 2.16)
0.15 (0.00 to 4.93)
0.72 (0.12 to 4.23)
0.96 (0.19 to 4.90)
7.31 (0.15 to 368.46)
7.47 (0.15 to 376.30)
7.15 (0.14 to 360.43)
0.05 (0.00 to 3.27)
7.59 (0.15 to 382.44)
0.13 (0.00 to 6.67)
3.88 (0.29 to 51.92)
0.14 (0.00 to 7.06)
0.14 (0.00 to 7.20)
0.05 (0.00 to 3.04)
0.27 (0.01 to 6.52)
0.14 (0.00 to 7.09)
2.14 (0.46 to 9.84)
0.09 (0.02 to 0.41)
0.81 (0.51 to 1.28)
7.55 (0.47 to 122.46)
1.98 (0.20 to 19.22)
0.90 (0.08 to 10.61)
4.76 (1.25 to 18.14)
1.06 (0.32 to 3.57)
3.85 (0.76 to 19.44)
7.08 (0.44 to 113.82)
7.92 (0.16 to 400.28)
7.09 (0.73 to 69.11)
1.04 (0.14 to 7.54)
0.14 (0.00 to 6.89)
2.39 (1.31 to 4.33)
1.21 (0.84 to 1.74)
1.5
0.8
2.6
3.4
0.9
1.3
1.3
5.6
5.1
0.9
3.1
1.6
1.7
1.1
4.2
5.0
0.9
0.9
0.9
0.8
0.9
0.9
2.0
0.9
0.9
0.8
1.3
0.9
5.7
5.3
62.7
1.7
2.6
2.2
7.4
9.0
5.0
1.7
0.9
2.6
3.4
0.9
37.3
100.0
0.01 0.1 010 100
Study
Increased
harm placebo
Increased
harm drugs
Peto odds ratio
xed (95% CI)
Peto odds ratio
xed (95% CI)
Weight
(%)
1/188
1/196
3/123
1/128
1/136
2/264
2/264
7/390
2/160
1/151
3/365
2/151
0/129
1/159
2/100
3/86
1/94
1/96
1/211
0/135
1/76
0/44
3/241
0/85
0/72
0/315
1/238
0/100
8/249
2/180
50/5126
2/48
2/109
2/71
8/93
8/187
5/104
2/165
1/100
3/97
2/92
0/94
35/1160
85/6286
Drugs
1/93
0/99
0/122
3/139
0/142
0/90
0/89
2/126
4/162
0/156
1/186
1/37
2/129
1/40
3/108
3/83
0/93
0/97
0/204
1/69
0/78
1/43
0/84
1/88
1/76
1/152
1/80
1/104
1/83
6/68
35/3120
0/48
1/110
1/32
1/87
4/99
1/102
0/157
0/107
0/91
2/96
1/95
11/1024
46/4144
Placebo
No of events/total
Fig | Meta-analysis of suicidality in participants receiving selective serotonin reuptake
inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) compared with
placebo post-randomisation
doi: 10.1136/bmj.i65 |
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2016;352:i65 | the bmj
RESEARCH
6
participants receiving imipramine, of which three in the
paroxetine group and two in the placebo group occurred
in the lead-out or post-treatment phase (table 4 ). Aggres-
sive behaviour occurred more often in the drug group com-
pared with placebo group (odds ratio 1.93, 95% confidence
interval 1.26 to 2.95). The odds ratio for adults was 1.09
(0.55 to 2.14) and for children and adolescents was 2.79
(1.62 to 4.81, figure 4). If data were removed from trials 28
and 34 (paediatric trials in which each centre had fraudu-
lent data), the increase in aggression remained: all ages
1.58 (1.00 to 2.51) and children and adolescents only 2.19
(1.17 to 4.11, see supplementary data D).
Only patient narratives were available for serious
events and they included homicidal threat, homicidal
ideation, assault, sexual molestation, and a threat to take
a gun to school (all five participants receiving sertraline),
damage to property, punching household items, aggres-
sive assault, verbally abusive and aggressive threats (all
five participants receiving paroxetine), and belligerence
(fluoxetine). Details were unavailable for non-serious
events, as they were either listed in adverse events tables
or given in the appendix of individual patient listings
without any narratives. These events were increased hos-
tility, aggressiveness, rage, or anger.
Akathisia
Thirty akathisia events occurred, all post-randomisa-
tion (22 in participants receiving study drugs, six in par-
ticipants receiving placebo, and two in participants
receiving clomipramine); two of the events, both in par-
ticipants receiving duloxetine, took place in the lead-
out phase (table 5 ). Akathisia occurred more often in
participants receiving the study drug than in those
receiving placebo (2.04, 0.93 to 4.48), but this dierence
was not statistically significant: for adults 2.00 (0.79 to
5.04) and for children and adolescents (2.15, 0.48 to 9.65,
fig 5). If data were removed from trial 70 (adults), where
some centres had fraudulent data, the odds ratio
becomes 1.99 (0.90 to 4.44) and for adults becomes 1.94
(0.75 to 4.99, see supplementary data D).
Some events were not listed as akathisia in the
adverse events tables because of the coding dictionar-
ies used. For example, in the three sertraline trials
where we had access to both the verbatim and the
coded preferred terms, akathisia seemed to have been
coded as “hyperkinesia” according to the World Health
Organisation Adverse Drug Reaction Terminology dic-
tionary. We could only identify akathisia if we had
access to the verbatim terms, which were sometimes
available from individual patient listings or patient nar-
ratives. For most duloxetine and fluoxetine trials,
akathisia was also noted in the regular adverse events
tables, and therefore the trials appeared to have more
events than those for other drugs for which akathisia
Table | Aggressive behaviour events in included trials, before and post-randomisation
Events Duloxetine Fluoxetine Paroxetine Sertraline Ve nlaf axine All drugs Placebo Imipramine
Before randomisation 3 0 0 0 0 3 2 0
Post-randomisation (any arm) 7 6 31 14 462 26 4
Total population 427 7 456 176 6 3165 1263 10 927 6832 76 7
Adults
Trial 04
Trial 05
Trial 06
Trial 07
Trial 09
Trial 10
Trial 11
Trial 16
Trial 30
Trial 31
Trial 32
Trial 38
Trial 39
Trial 44
Trial 45
Trial 49
Trial 53 and 54
Trial 58
Trial 63
Trial 64
Trial 67
Trial 68
Subtotal (95% CI)
Test for heterogeneity:
χ2=23.60, df=21,
P=0.31, I
2=11%
Test for overall eect: z=0.24, P=0.81
Children and adolescents
Trial 24
Trial 25
Trial 26
Trial 27
Trial 28
Trial 29
Trial 33
Trial 34
Trial 42
Trial 43
Trial 56
Subtotal (95% CI)
Test for heterogeneity:
χ2=10.67, df=10,
P=0.38, I
2=6%
Test for overall eect: z=3.70, P<0.001
Total (95% CI)
Test for heterogeneity:
χ2=38.80, df=32,
P=0.19, I
2=18%
Test for overall eect: z=3.04, P=0.002
Test for subgroup dierences:
χ2=4.53,
df=1, P=0.03, I
2
=77.9%
4.50 (0.07 to 285.95)
0.51 (0.05 to 4.91)
0.39 (0.05 to 2.84)
7.78 (0.48 to 125.09)
3.82 (0.16 to 93.42)
0.13 (0.01 to 2.13)
0.02 (0.00 to 1.60)
7.52 (0.15 to 379.06)
1.01 (0.06 to 16.26)
7.64 (0.15 to 385.12)
0.48 (0.03 to 9.08)
3.47 (0.03 to 480.43)
0.13 (0.01 to 2.16)
8.00 (0.16 to 404.57)
7.14 (0.14 to 359.84)
4.53 (0.07 to 285.39)
3.85 (0.04 to 338.83)
3.82 (0.04 to 344.50)
7.81 (0.15 to 394.22)
7.20 (0.45 to 115.73)
0.02 (0.00 to 1.72)
0.53 (0.05 to 5.16)
1.09 (0.55 to 2.14)
0.14 (0.00 to 6.82)
1.01 (0.28 to 3.58)
4.27 (0.06 to 294.70)
7.41 (1.64 to 33.47)
4.67 (0.43 to 50.76)
7.32 (0.45 to 117.83)
2.28 (0.51 to 10.17)
6.01 (1.79 to 20.19)
7.09 (0.73 to 69.11)
1.04 (0.06 to 16.82)
1.36 (0.30 to 6.12)
2.79 (1.62 to 4.81)
1.93 (1.26 to 2.95)
1.0
3.5
4.6
2.3
1.8
2.3
0.9
1.2
2.3
1.2
2.1
0.7
2.3
1.2
1.2
1.0
0.9
0.9
1.2
2.3
0.9
3.5
39.3
1.2
11.2
1.0
7.9
3.2
2.3
8.0
12.2
3.5
2.3
7.9
60.7
100.0
0.01 0.1 010 100
Study
Increased
harm placebo
Increased
harm drugs
Peto odds ratio
xed (95% CI)
Peto odds ratio
xed (95% CI)
Weight
(%)
1/196
1/123
1/128
2/136
2/264
0/89
0/390
1/227
1/160
1/151
1/365
1/151
0/129
1/100
1/86
1/135
1/241
1/132
1/72
2/157
0/238
1/100
21/3770
0/48
5/109
1/71
7/93
3/187
2/104
5/165
10/100
3/97
1/92
4/94
41/1160
62/4930
Drugs
0/99
2/122
3/139
0/142
0/89
2/88
1/126
0/231
1/162
0/156
1/186
0/37
2/129
0/108
0/83
0/69
0/84
0/45
0/76
0/152
1/80
2/104
15/2507
1/48
5/110
0/32
0/87
0/99
0/102
2/157
1/107
0/91
1/96
3/95
13/1024
28/3531
Placebo
No of events/total
Fig | Meta-analysis of aggressive behaviour in patients receiving selective serotonin
reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs)
compared with placebo post-randomisation
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RESEARCH
7
was miscoded—for example, no cases of akathisia were
reported in the paroxetine trials. These events would be
missed in trials where such detailed information was
not available. Therefore our number of akathisia events
is likely to be an underestimate, as the event appeared
to be have been coded under many other activation
terms, such as irritability, agitation, or nervousness.
Comparison of our data with the summary trial
reports on Eli Lilly’s website
Information was limited on adverse events in these
summary reports and it was not reliable. The number of
serious events was always mentioned but the cases
were not always explained and the reports focused on
the most common adverse events. All reports contained
tables of treatment emergent adverse events, but not for
all patients (with the exception of trials 23 and 26 where
complete data were tabulated), and in most cases the
events were only shown if they occurred in, for exam-
ple, at least 5% of patients. We were unable to find the
online summary reports for four trials (trials 19-22, all
on duloxetine). All the eight deaths (six in participants
receiving duloxetine and two in participants receiving
placebo) post-randomisation were noted in the online
summaries, although information on one suicide in a
participant receiving duloxetine in the open label phase
before randomisation in trial 7 was missing, as no data
from that phase were available online. Only two (both
participants receiving fluoxetine) of the 20 suicide
attempts (14 participants receiving duloxetine, three
fluoxetine, and three placebo) were documented in the
summaries, and none of the 14 suicidal ideation events
(eight in participants receiving duloxetine, two paroxe-
tine, one fluoxetine, and three placebo) were men-
tioned. Only 10 (three participants receiving fluoxetine
and seven placebo) of the 25 aggressive behaviour
events (five participants receiving duloxetine, six fluox-
etine, and 14 placebo) were found online. Only three
akathisia events (all participants receiving fluoxetine)
of the 17 (10 receiving duloxetine, five fluoxetine, and
two placebo) were in the summaries. However, the case
of the “elevated liver enzymes” in a patient receiving
fluoxetine in trial 26 was clarified as an intentional
overdose.
Discussion
Systematic reviews of harms are needed for a balanced
view of medical interventions, particularly to elucidate
the occurrence of rare but serious events.34 Clinical
study reports are far more reliable than published trial
reports,2 4 28 but even using these we were unable to
unravel the true number of serious harms. The trials
had many shortcomings, in both the design and the
reporting of the trials in the clinical study reports, and
therefore our numbers are likely to be underestimates.
The summary reports on Eli Lilly’s website were even
more unreliable than we previously suspected.28 Only
mortality had (almost) complete information.
Comparison with other studies
We found no significant dierences in mortality or sui-
cidality overall, but our data confirmed the increased
risk of suicide in children and adolescents.5 16 We wanted
to clarify these risks in adults and found no significant
increase in association with drugs, similar to previous
analyses.7 8 Our results however, cannot be compared
easily with the results of the 2006 FDA meta-analysis7 as
we had data from 18 526 patients, whereas the FDA
included about 100 000 patients. The FDA did not con-
sider the limitations of the trials that we identified and
introduced some of their own—for example, by only
counting events within 24 hours after the randomised
phase was over. We counted all post- randomisation
events in our study, although they were not always
available. Interestingly, an FDA employee published a
Table | Akathisia events in included trials, post-randomisation (no events noted previously)
Drug (any arm) Duloxetine Fluoxetine Sertraline Venlafaxine All drug s Placebo Clomipramine
Akathisia events 12 7 2 1 22 6 2
Total population 4277 456 316 5 1263 10 927 6832 767
Adults
Trial 01
Trial 02
Trial 05
Trial 08
Trial 09
Trial 10
Trial 11
Trial 49
Trial 53 and 54
Trial 70
Subtotal (95% CI)
Test for heterogeneity:
χ2=8.56, df=9,
P=0.48, I
2=0%
Test for overall eect: z=1.47, P=0.14
Children and adolescents
Trial 24
Trial 25
Trial 26
Trial 42
Subtotal (95% CI)
Test for heterogeneity:
χ2=3.58, df=3,
P=0.31, I
2=16%
Test for overall eect: z=1.00, P=0.32
Total (95% CI)
Test for heterogeneity:
χ2=12.15, df=13,
P=0.52, I
2=0%
Test for overall eect: z=1.77, P=0.08
Test for subgroup dierences:
χ2=0.01,
df=1, P=0.94, I
2
=0%
5.47 (0.54 to 55.61)
0.12 (0.00 to 6.28)
7.33 (0.15 to 369.38)
4.55 (0.07 to 285.11)
4.55 (0.41 to 50.48)
7.39 (0.46 to 119.09)
0.36 (0.06 to 2.06)
4.53 (0.07 to 285.39)
3.85 (0.04 to 338.83)
3.97 (0.05 to 320.94)
2.00 (0.79 to 5.04)
1.00 (0.06 to 16.22)
7.60 (0.78 to 73.80)
4.27 (0.06 to 294.70)
0.13 (0.00 to 6.40)
2.15 (0.48 to 9.65)
2.04 (0.93 to 4.48)
11.5
4.0
4.0
3.6
10.7
8.0
20.6
3.6
3.1
3.2
72.5
8.0
12.0
3.5
4.0
27.5
100.0
0.01 0.1 010 100
Study
Increased
harm placebo
Increased
harm drugs
Peto odds ratio
xed (95% CI)
Peto odds ratio
xed (95% CI)
Weight
(%)
3/103
0/82
1/123
1/175
3/177
2/89
4/390
1/135
1/241
1/180
17/1695
1/48
3/109
1/71
0/97
5/325
22/2020
Drugs
0/70
1/75
0/122
0/90
0/89
0/88
3/126
0/69
0/84
0/68
4/881
1/48
0/110
0/32
1/91
2/281
6/1162
Placebo
No of events/total
Fig | Meta-analysis of akathisia in participants receiving selective serotonin reuptake
inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) compared with
placebo post-randomisation
doi: 10.1136/bmj.i65 |
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2016;352:i65 | the bmj
RESEARCH
8
paper in 2001 using FDA data that showed 22 suicides in
22 062 patients randomised to antidepressants,35 which
equates to 10 per 10 000 population, but in the large FDA
meta-analysis five years later, five suicides were reported
in 52 960 patients, or 1 per 10 000 population.7
A review with over 40 000 patients using data sub-
mitted to the UK’s Medicines and Healthcare products
Regulatory Agency (MHRA) also found no increased
risk for suicidality in adults using serotonin reuptake
inhibitors (SSRIs), but noted that the relative frequency
of reported self harm and suicidal thoughts in the trials
compared with suicide indicated that non-fatal end-
points were under-recorded.8 Another review, with
87 650 patients (all ages), reported a doubling in the
odds of suicide attempts, which was statistically signif-
icant,1 in contrast with our findings in adults. As with
our study, both reviews found serious limitations in the
trials and evidence of under-reporting of serious harms.
This under-reporting was also confirmed in the recent
republication by independent investigators of study 329
of paroxetine in children and adolescents.36 We did not
get access to the appendices of this trial, which contained
the individual patient listings. Many suicidal events were
only documented there, and even more suicidal events
were only identified in the case report forms, which the
investigators got access to after protracted negotiations
with GlaxoSmithKline and then only through a single
screen remote desktop interface, which made it impossi-
ble for the researchers to review all 77 000 pages.36
We found that the risk of aggressive behaviour was
doubled with use of antidepressants (all ages), which
was a statistically significant result, but when we
restricted our analysis to adults, there was no such eect.
However, we did find a doubling of risk for children and
adolescents, which is consistent with the increased inci-
dence in hostility noted by the MHRA.16 We found that
akathisia was much under-reported. Akathisia occurred
more often in participants receiving drugs than receiving
placebo, both in children and adolescents and in adults,
but the dierence was not significant (all ages, odds ratio
2.04, 95% confidence interval 0.93 to 4.48). We also found
similar results in a systematic review of trials in healthy
adult volunteers that included data from 10 published
trials and two unpublished trials (clinical study reports
obtained from EMA). Compared with placebo (n=226),
antidepressants (n=318) were associated with an
increased rate of activation or other precursor events for
aggression and suicidality (odds ratio 1.81, 95% confi-
dence interval 1.05 to 3.12).37
Limitations in the trials and clinical study reports
In most trials (86%), patients were only randomised if
they failed to improve in the placebo lead-in period.
One large trial had a 12 week open label period where
533 patients received duloxetine and only 278 patients
(52%) who tolerated the drug were randomised. This
gives rise to response based selection bias, which has
an impact on the subsequent randomised phase.
During that open label period for duloxetine, there was
one suicide (by hanging), four suicide attempts, and
four suicidal ideation events.
Another problem was insucient lead-in periods.4 24 At
least 36 trials had insucient wash-out periods, lasting
for only a few days or a week. An additional nine trials
had no lead-in period. Even when a placebo lead-in
period was specified it was not always adhered to—for
example, in a venlafaxine trial (trial 70), the wash-out
period was inadequate in 30 patients who received drugs
before the study, and in a sertraline trial (trial 50) it was
stated that “some patients proceeded to double-blind
treatment without a prior placebo run-in.” As patients are
often receiving treatment with similar drugs already,
some may develop withdrawal eects when they are
switched to a placebo,2 4 12 14 23 24 which can be wrongly
counted as adverse events. These iatrogenic harms can be
substantial. In a large study supported by Eli Lilly, with-
drawal symptoms were registered in patients during a 5-8
day period; 4-24 months after their depression had remit-
ted. Placebo was substituted for active drug, unknown to
the patients, and when the patients were switched to pla-
cebo, about one third receiving sertraline or paroxetine
became agitated, irritable, reported worsened mood, and
their Hamilton depression score increased by at least 8.38
Most trials did not report on post-treatment events.
As previously noted, the FDA included events occur-
ring within the first 24 hours after the randomised
phase ended.7 For sertraline trials in adults (the
report’s table 30; we reanalysed this summary data),
there was no increased risk of suicide or suicide
attempts (risk ratio 0.87, 95% confidence interval 0.31
to 2.48).7 When Pfizer analysed its trial data, the
results looked much better for sertraline (we reanal-
ysed their data for suicide or suicide attempts); risk
ratio 0.52 (0.17 to 1.59).39 However, Pfizer published an
additional analysis where the patients were followed
up for 30 days after the randomised phase ended and
then sertraline did not seem to protect against suicides
or suicide attempts in adults but rather seemed to
cause them (we reanalysed their data, risk ratio 1.47,
0.77 to 2.83), even though these findings were not sig-
nificant.39 The investigators who used MHRA data8
found that when events after 24 hours were included,
the risk of suicide or self harm was doubled with ser-
traline: we reanalysed the data (risk ratio 2.14, 0.96 to
4.75), although the finding was not statistically signif-
icant (see supplementary data D).7
Another limitation was the use of dierent coding
dictionaries; 32 trials (46%) did not state which one
they used. Sixteen of the sertraline trials used the World
Health Organisation Adverse Drug Reaction Terminol-
ogy, and as it does not allow for coding of akathisia or
suicidal ideation, such events are most likely to be
underestimated in our review. Furthermore, we found
that many suicidal ideation events were coded as
“worsening depression” or “emotional lability” in treat-
ment emergent adverse events tables in the paroxetine
trials, which used their own dictionary (the Adverse
Drug Experience Coding System, ADECS), as has been
noted by other studies.36 40 Only one trial (trial 27) men-
tioned this problem in the clinical study report, which
stated that “emotional lability captures events such as
suicidal ideation/gestures as well as overdoses.” We
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RESEARCH
9
could not find any akathisia events in the paroxetine
trials, as we did not have access to the verbatim terms
and the events were coded as other activation terms
despite akathisia being the preferred term in the Coding
Symbols for a Thesaurus of Adverse Reaction Terms dic-
tionary, on which ADECS is based.41
Minor tranquillisers and sleeping aids were used in
many of the studies, which tend to obscure aggression
and akathisia events. Additionally, two thirds of all tri-
als excluded patients at risk of suicide.
Strengths and limitations of this review
We believe ours is the first comprehensive review of ran-
domised controlled trial data using clinical study
reports for aggressive behaviour and akathisia, and our
finding of the doubling of aggression in children and
adolescents is novel. Our review has highlighted limita-
tions in the trials, not only in their design but also in
their reporting in the clinical study reports, which may
have led to serious under-estimation of the harms.
A main limitation of our review was that the quality of
the clinical study reports diered vastly and ranged
from summary reports to full reports with appendices,
which limited our ability to detect the harms. Our study
also showed that the standard risk of bias assessment
tool was insucient when harms from antidepressants
were being assessed in clinical study reports. Most of the
trials excluded patients with suicidal risk and so our
numbers of suicidality might be underestimates com-
pared with what we would expect in clinical practice.
We also did not have access to case report forms and
because of coding problems we deliberately took a con-
servative approach and used only one term for identify-
ing akathisia.
Conclusions and implications for research and
practice
We believe our study shows that, despite using clinical
study reports, the true risk for serious harms is still
uncertain. The low incidence of these rare events and
the poor design and reporting of the trials makes it dif-
ficult to get accurate eect estimates.
The FDA has advised that antidepressants may also
cause suicide in young adults (18 to 24 years) and recom-
mends that “patients of all ages” treated with antide-
pressants should be monitored for “clinical worsening,
suicidality, and unusual changes in behaviour.”42
GlaxoSmithKline also issued letters to doctors, inform-
ing them about the increased harm in young adults6 and
admitted that for adults with depression “(all ages), the
frequency of suicidal behaviour was higher in patients
treated with paroxetine compared with placebo: 11/3455
(0.32%) versus 1/1978 (0.05%).”43 A cohort study from
Sweden recently showed an increase in violent crime in
young adults taking antidepressants (hazard ratio 1.43,
95% confidence interval 1.19 to 1.73).44
Therefore we suggest minimal use of antidepressants
in children, adolescents, and young adults, as the seri-
ous harms seem to be greater, and as their eect seems to
be below what is clinically relevant.4 45-47 Alternative
treatments such as exercise48 49 or psychotherapy4 50 may
have some benefit and could be considered, although
psychotherapy trials also suer from publication bias.51
The need for identifying hidden information in clini-
cal study reports to form a more accurate view of the
benefits and harms of drugs has been highlighted by the
Restoring Invisible and Abandoned Trials (RIAT) initia-
tive,52 and the recent revised version of trial 329.36 More
data from clinical study reports are expected to become
available in the coming years, with the EMA’s new policy
to make all newly submitted reports publicly available.53
As it can be quite labour intensive to perform systematic
reviews using clinical study reports, more reliable auto-
mated methods for text mining are needed, such that all
data, including that from individual patient listings and
case report forms, can be routinely considered.36 54
We thank the European Medicines Agency and Medicines and
Healthcare products Regulatory Agency for providing the clinical study
reports used for this review. Some results of this study were presented
at the Research waste/EQUATOR conference in Edinburgh, Scotland
(September 2015).
Contributors: All authors had complete access to the data in the
study. LSG was known by her maiden name Jensen at the time of the
study. TS and PCG contributed to the study concept and design, wrote
the protocol, and obtained funding. TS, LSG, and NF acquired the data
for the study; all authors contributed to the analysis and/or
interpretation of data. TS developed the rst dra of the manuscript
and all authors critically revised the manuscript and approved the nal
version. PCG is the study supervisor and guarantor.
Funding: This study is part of a PhD (TS) thesis, funded by the Laura
and John Arnold Foundation. The funding source had no role in the
design and conduct of the study; data collection, management,
analysis, and interpretation; preparation, review, and approval of the
manuscript; or the decision to submit the paper for publication.
Competing interests: All authors have completed the ICMJE uniform
disclosure form at http://www.icmje.org/coi_disclosure.pdf (available
on request from the corresponding author) and declare: this study is
part of a PhD funded by the Laura and John Arnold Foundation for lead
author (TS); no nancial relationships with any organisations that
might have an interest in the submitted work in the previous three
years; no other relationships or activities that could appear to have
influenced the submitted work.
Ethical approval: Not required.
Transparency: The lead author (TS) and study guarantor (PCG) arm
that the manuscript is an honest, accurate, and transparent account of
the study being reported. No important aspect of the study has been
omitted. No discrepancies are withheld.
Data sharing: Additional data and the clinical study reports can be
obtained from the corresponding author on request.
This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license,
which permits others to distribute, remix, adapt, build upon this work
non-commercially, and license their derivative works on dierent
terms, provided the original work is properly cited and the use is
non-commercial. See: http://creativecommons.org/licenses/
by-nc/3.0/.
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Web extra material
Supplementary data A: additional details on methods
Supplementary data B: trial characteristics of included
70 randomised controlled trials
Supplementary data C: case notes for primary outcomes
Supplementary data D: additional analyses
