Selective serotonin reuptake inhibitors
BMJ 2004; 329 doi: https://doi.org/10.1136/bmj.329.7470.809 (Published 07 October 2004) Cite this as: BMJ 2004;329:809
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21/12/04 Response to Geddes leader in BMJ
Sir
Geddes (BMJ 329, 809-810) comments that available randomised evidence
does not provide reliable estimates of the costs and benefits of SSRI
treatment in patients with varying levels of severity and baseline risk of
suicide. He also laments that non-commercial funding for trials is
declining. The recently published NICE guidance on depression is also
woefully short of evidence, with most of the recommendations graded only
“C” (so called “level IV evidence” which is expert opinion or clinical
experience, and not research evidence). Both he and the authors of the
guidance may therefore be pleased to learn that the Health Technology
Assessment programme is indeed funding a trial to address this very
question. Led by the University of Southampton, in partnership with the
University of Liverpool and Institute of Psychiatry, the “THREAD” trial is
investigating the effectiveness of SSRIs combined with supportive care,
versus supportive care alone, in exactly this patient population.
Since the paper by Paykel and colleagues in 19881 suggested that
severity of depression around the threshold of DSM major depressive
episode was the level at which antidepressant drugs were more effective
than placebo, two recent studies have suggested that SSRI antidepressants
may be effective in patients with depressive symptoms of lesser
severity2,3. Confusion results from the inexact use of terminology in
this field – what is described in the NICE guidance as “mild” depression
is actually subsyndromal depression by the lights of ICD 10 criteria. The
“THREAD” study is utilizing a continuous measure of symptom severity, the
Hamilton Depression Rating Scale, as its chief predictor variable, and
recruiting patients with a score of 12 or more, all therefore likely to
lie in at least the “moderate” range according to NICE terminology.
One finding of the trial already apparent however is that patient and
doctor preferences make randomization a difficult proposition in this
context. As has already been observed in previous trials of counselling
and drug treatment in this population, truly randomised evidence may only
be obtainable in a group of participants who are unusual in other
respects, and we need to learn more about the strengths and weaknesses of
randomised and preference designs for investigating the value of
treatments in such contexts4.
1. Paykel ES, Hollyman JC, Freeling P, Sedgwick P. Predictors of
therapeutic benefit from amitriptyline in mild depression: a general
practice placebo-controlled trial. J Affective Dis 1988; 14: 83-95
2. Judd LL, Rapaport MH, Yonkers KA, Rush AJ, Frank E, Thase ME,
Kupfer DJ, Plewes JM, Schettler PJ, Tollefson G. Randomized placebo-
controlled trial of fluoxetine for acute treatment of minor depressive
disorder. Amer J Psychiatry 2004; 161: 1864-1871.
3. Barrett JE, Williams JW, Oxman TE, Frank E, Katon W, Sullivan M,
Hegel MT, Cornell JE, Sengupta AS. Treatment of dysthymia and minor
depression in primary care: a randomized trial in patients aged 18 to 59
years. Journal of Family Practice 2001; 50: 405-412.
4. Bedi N, Chilvers C, Churchill R, Dewey M, Duggan C, Fielding K,
Gretton V, Miller P, Harrison G, Lee A, Williams I. Assessing
effectiveness of treatment of depression in primary care. Partially
randomised preference trial. Br J Psychiatry 2000; 177: 312-318.
Robert Peveler and Tony Kendrick,
University of Southampton
On behalf of the “THREAD” study group
Competing interests:
Robert Peveler has received hospitality, and fees for speaking and consultancy from Lilly, Glaxo SmithKline and Lundbeck, and research funds from the Department of Health
Competing interests: No competing interests
Geddes and Cipriani aim to restore some balance in the debate about
the risks of antidepressants.1 They claim that based on the evidence, the
suicide risk of selective serotonin reuptake inhibitors (SSRIs) is blown
out of proportion by the media. The methodological question they raise is:
what can be considered ‘best evidence’ in antidepressant trials? They fear
that regulatory bodies may overrate the importance of placebo-controlled
trials. Their head to head comparison to the older tricyclic
antidepressants indicates that SSRIs are of comparable efficacy.2
We disagree with Geddes and Cipriani and agree with the regulatory bodies.
The placebo controlled randomised trial is still the best test of efficacy
available. To put the methodological quality of the evidence about the
risks of antidepressants into perspective, Geddes and Cipriani describe
several already known types of biases, such as publication bias.
Recent meta-analyses show that the list of factors, and methodological
flaws, which may bias the contrast of antidepressant drugs versus placebo
is already quite long.3;4 However, differential selection bias by using a
placebo washout period has not yet been addressed.
Most antidepressant trials and especially the older ones have used
such a placebo washout period before randomisation. To demonstrate the
effects of placebo washouts: say 200 patients are available for a study,
and 20 placebo responders are excluded. The remaining 180 patients are
then randomised to antidepressant or placebo treatment. Without the
placebo wash out period, the ten excluded placebo-responders in the
placebo arm would all have been considered to have been recovered.
However, as it is not known whether all placebo responders in the
antidepressant arm would recover, the direction of this differential
selection favours antidepressants. Clinically, exclusion of placebo
responders appears logical. Our contention is however, that this custom
may also help to inflate the effects of antidepressants. Randomisation is
meant to provide sufficient evidence for the doctor in the surgery for the
decision whether this class of patients (with major depression) benefits
from an antidepressant prescription. Few GPs use a placebo washout in real
life practice.
Other known potential biases are: a) time: over the years, placebos become
more effective;3 4 b) type of placebo: the use of ‘active’ placebo’s,
which allow better blinding as they contain substances that mimic the
specific side-effects of antidepressants, diminishes the effectiveness of
antidepressant drugs, whereas most conventional trials use inert
placebos,5 c) a lack of concealment of allocation, yielding larger
estimates of treatment effect6 7, d) a lack of independent outcome
assessment, e) exclusion effects: many relevant groups such as older
patients are excluded from trials, and f) type of analysis: consistent use
of the more conservative and therefore more real-life intention-to-treat
(ITT) analyses in stead of per-protocol (PP) analyses decreases the risk
difference between antidepressant drugs and placebo from 28% to 19%.8
Several other potential biases have been suggested, such as setting
effects, as remarkably few studies have been performed in primary care,
and funding effects as almost all studies were sponsored by pharmaceutical
industries.6
A large, independently funded, good quality general practice trial of
antidepressants versus placebo is much needed now, without placebo
washouts.
Reference List
1. Geddes JR, Cipriani A. Selective serotonin reuptake inhibitors.
BMJ 2004;329:809-10.
2. Geddes JR, Freemantle N, Mason J, Eccles MP, Boynton J. SSRIs versus
other antidepressants for depressive disorder. Cochrane Database Syst Rev
2000;CD001851.
3. Stolk P, ten Berg MJ, Hemels ME, Einarson TR. Meta-Analysis of Placebo
Rates in Major Depressive Disorder Trials. Ann Pharmacother 2003;37:1891-
9.
4. Walsh BT, Seidman SN, Sysko R, Gould M. Placebo response in studies of
major depression: variable, substantial, and growing. JAMA 2002;287:1840-
7.
5. Moncrieff J, Wessely S, Hardy R. Active placebos versus antidepressants
for depression. Cochrane.Database.Syst.Rev. 2004;CD003012.
6. MacGillivray S, Arroll B, Hatcher S, Ogston S, Reid I, Sullivan F et
al. Efficacy and tolerability of selective serotonin reuptake inhibitors
compared with tricyclic antidepressants in depression treated in primary
care: systematic review and meta-analysis. BMJ 2003;326:1014.
7. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias.
Dimensions of methodological quality associated with estimates of
treatment effects in controlled trials. JAMA 1995;273:408-12.
8. Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I, et al. Improving
the quality of reporting of randomized controlled trials: the CONSORT
statement. JAMA 1996;276:637-9.
Competing interests:
None declared
Competing interests: No competing interests
I agree with much of Geddes & Cipriani's editorial on selective serotonin reuptake inhibitors,1 including their caution, as the full evidence is not yet available, that SSRIs can cause suicide. The editorial coincided with the third Panorama programme on the potential dangers of Seroxat. This TV programme focused less than the previous two on discontinuation problems.w1,w2 For some reason, the editorial does not mention discontinuation problems at all.
Geddes & Cipriani note that the draft NICE guideline seems to be moving to what may be a controversial conclusion of a greater antidepressant/placebo difference with increasing severity of depression. Much of this evidence comes from data on outpatients. There needs to be caution about misinterpreting effects which are due to regression to the mean that almost always produces a correlation between baseline scores and change scores.2, w3 Also, inpatients may do worse than outpatients and one study of hospitalised patients found those with nonpsychotic moderate depression did better on antidepressants than those with nonpsychotic severe or psychotic depression.3 Few studies have been conducted in general practice. One that was found tricyclic antidepressants to be of benefit in a spectrum of milder depressions, except for the most mild cases.4
The central issue is the extent to which antidepressant trials hide amplified placebo effects. Geddes & Cipriani seem prepared to consider the conclusion that SSRIs do not work much better than placebo. This has potentially extraordinary implications for clinical practice, yet Geddes & Cipriani suggest that the SSRI data may be misleading, but then do not explain in what way it is misleading. They propose that data on comparable efficacy with tricyclic antidepressants needs to be considered, but an alternative conclusion is that tricyclic antidepressants, like SSRIs, are little better than placebo.w4
Too much emphasis is placed on short term trials. This is why the data on discontinuation problems is important. People treated without antidepressants may do better over the long term. There is some naturalistic evidence to support this view.5 People who recover without antidepressants may manage to work through their problems, avoiding the reliance on medication reflected in discontinuation symptoms. As Geddes & Cipriani note, independent trials are needed to tease out these issues. Maybe this requires no longer permitting drug companies to control clinical testing of their own drugs.
- Geddes JR, Cipriani A. Selective serotonin re-uptake inhibitors remain useful drugs which need careful monitoring. BMJ 2004; 329: 809-810 (9 October) [Full text]
- Kirsch I, Scoboria A & Moore TJ. Antidepressants and placebos: Secrets, revelations, and unanswered questions.Prevention and Treatment.5, Article 33, posted July 15, 2002 http://www.journals.apa.org/prevention/volume5/pre0050033r.html
- Kocsis JH, Croughan JL, Katz MM et al. Response to treatment with antidepressants of patients with severe or moderate non- psychotic depression and of patients with psychotic depression. American Journal of Psychiatry 1990; 147: 621-624.
- Paykel ES, Freeling P, Hollyman JA. Response to treatment with antidepressants of patients with severe or moderate nonpsychotic depression and of patients with psychotic depression. Pharmacopsychiatry 1988; 21: 15-18.
- Brugha TS, Bebbington PE, MacCarthy B, Sturt E, Wykes T. Antidepressants may not assist recovery in practice: a naturalistic prospective survey. Acta Psychiatrica Scandinavica. 1992; 86: 5-11.
w1. Double DB. The facts of antidepressant discontinuation reactions. bmj.com/cgi/eletters/325/7369/910#26377, 20 October 2002 [Full text]
w2. Double DB. What does it mean to say that antidepressants have helped millions of people round the world? bmj.com/cgi/eletters/326/7398/1093#32503, 21 May 2003 [Full text]
w3. Critical Psychiatry Network comments on NICE depression clinical guideline - first draft. www.critpsynet.freeuk.com/NICE1stdepression.htm [Full text]
w4. Moncrieff J. Evidence for older antidepressants shaky too. bmj.bmjjournals.com/cgi/eletters/329/7470/809#80243, 21 October 2004 [Full text]
Competing interests:
None declared
Competing interests: No competing interests
In contrast to Geddes and Cipriani’s assertion that there is a “lack
of clinical uncertainty about the efficacy of existing drugs for
depression” (1) a careful look at the evidence suggests that even the
efficacy of tricylic and other older generation antidepressants is far
from proven. Although many placebo controlled trials show tricylcic
antidepressants (TCAs) to be superior to placebo there are also a great
number that don’t. Most importantly some of the largest and best conducted
older trials find no difference between antidepressants and placebo on
primary outcomes (2,3). In addition aspects of the methodology and
presentation of antidepressant trials are likely to have inflated the
apparent superiority of antidepressants (4):
1) The obvious side effects of antidepressants, especially tricyclics, are
likely to have unblinded placebo controlled trials using ordinary inert
placebos
2) Many depression rating scales contain items such as sleep and
agitation, which are likely to respond to non specific sedative effects of
antidepressant drugs. Since differences between drugs and placebo
frequently amount to only a few points on rating scales it is clear that
antidepressants may appear superior to placebo due to these effects alone.
3) Many trials use categorical outcomes which may inflate drug placebo
differences.
4) Positive outcomes may be selectively reported and negative ones
ignored
5) Analysis techniques such as excluding withdrawals may inflate drug
placebo differences
6) There is likely to be publication bias
The fact that many agents not classified as antidepressants including
benzodiazepines, barbiturates, buspirone and various antipsychotics have
been found to be superior to placebo or equivalent to antidepressants in
some randomised trials suggests that antidepressant effects may indeed be
attributable to non specific pharmacological or psychological factors (4).
Finally the lack of substantial differences between antidepressants
and placebo in trials and meta-analyses cannot be explained away by
suggesting that effects are diluted by inclusion of patients with mild
conditions. Traditionally these are thought to be less responsive to
antidepressants compared with more severe conditions. However, this has
not been clearly demonstrated. The NICE meta-analysis, contrary to its
assertions, does not find a clear gradient of effects from mild to severe
depression (5). A recent meta-analysis which revealed very small
differences between a range of new antidepressants and placebo (a mean of
2 points on the Hamilton Rating Scale for Depression) was conducted with
patients with at least moderate and mainly severe depression by modern
standards (6). My meta-analysis of older antidepressant trials found that
differences between antidepressants and placebo were small and not
statistically significant in trials of inpatients compared with larger
effects seen in outpatient trials (7).
If we ditch the assumption that tricyclic and older generation
antidepressants have been demonstrated to be effective, then the anomalies
referred to by Geddes & Cipriani (1) are explained. It is clear why
selective serotonin re-uptake inhibitors and TCAs are comparable. Neither
of them have been demonstrated to have specific “antidepressant” effects.
Both are not consistently distinguishable from placebo and the superiority
sometimes observed may be attributable to non-specific effects or other
methodological artefacts.
Yours etc,
1 Geddes JR, Cipriani A. Selective serotonin re-uptake inhibitors
remain useful drugs which need careful monitoring. BMJ 2004;329:809-810.
2 Medical Research Council. Clinical trial of the treatment of
depressive illness.
BMJ 1965; 1: 881-886.
3 Raskin A, Schulterbrandt JG, Reatig N, Chase C, McKeon JJ.
Differential response to chlorpromazine, imipramine and placebo. Arch Gen
Psych 1970; 23: 164-173.
4 Moncrieff J. Are antidepressants over-rated? A review of
methodological problems in antidepressant trials. JNMD 2001;189:288-295.
5 National Institute for Clinical Excellence (NICE) (2003)
Depression clinical guideline- second consultation. www.nice.org.uk
6 Kirsch I (2002) The emperor’s new drugs: an analysis of
antidepressant medication data submitted to the US Food and Drug
Administration. Prevention and Treatment, 5, available at
http://journals.apa.org/prevention.
7 Moncrieff J. A comparison of antidepressant trials using active
and inert placebos. Int J Methods Psychiatric Research 2003;12:117-127.
Competing interests:
None declared
Competing interests: No competing interests
Even though I suffered intense anxiety, panic attacks and suicidal
ideation when I tried fluoxetine as a medical student 10 yrs ago I do not
want to see the class of drugs demonised.
I warn patients about feeling worse before feeling better and they
rarely have problems. They know it will pass as a bad trip and aren't
terrified of it being them 'losing grip despite treatment'. To my surprise
those with bad start ups still opted to use the drugs again later and had
no problems second time around.
It took me 10 years to try any antidepressants after the experience.
Now I have found citalopram. Easy on, easy off. However mild depression is
on scoring it has impact on daily life and these drugs do make a
personally significant difference even if the questions asked to rate
depression aren't sensitive enough to pick it up as statistically
different.
Competing interests:
None declared
Competing interests: No competing interests
Clinicians know that randomised controlled trials (RCTs) are far away
from
applied pharmacotherapy in the real world. To compare the efficacy of an
antidepressant with placebo in a drug trial is a very different matter
from
prescribing an antidepressant to a depressed patient in the context of a
therapeutic relationship. Medical professionals in clinical practice have
no
doubts that antidepressants can do a wonderful job when prescribed for the
right diagnosis in the right way, on the basis of a trusting patient-
doctor
relationship. Krupnick et al. (1) nicely demonstrated the importance of
the
therapeutic alliance in pharmacotherapy. Obviously, in a double-blind RCT,
the therapeutic alliance in regard to the role of the drug in an
individual
treatment – assuming that no sane clinician sees himself as a robot simply
issuing prescriptions – is deeply affected. Unfortunately, this aspect is
usually
neglected when conclusions are drawn from RCTs.
Konrad Michel, Bern
1) Krupnick, J.L., Sotsky, S.M., Simmens, S., Moyer, J. The role of
the
therapeutic alliance in psychotherapy and pharmacotherapy outcome:
Findings in the National Institute of Mental Health treatment of
depression
collaborative research program. Journal of Consulting and Clinical
Psychology
1996, 64, 532-539.
Competing interests:
None declared
Competing interests: No competing interests
Contrary to Geddes and Cipriani’s blanket assertions<1> it is
time to stop shooting the messengers and face the evidence that, at least
for depressed children and adolescents, antidepressants do more harm than
good.<3> The belief that antidepressants are beneficial for children
and adolescents appears to be based on misunderstanding the observational
and clinical trial evidence and misinterpretation of clinical experience.
Geddes and Cipriani claim that observational evidence implies “SSRIs
are not a major cause of suicide.” However increased SSRI use has neither
been proven nor excluded as the cause of increased suicides amongst
Australian females aged 15-44 and males aged 24-44.<2> Reliable data
for children are not available.
Of 17 trials of drugs for major depression in children and
adolescents only one has been positive on the primary
endpoint.<3,4,5> The misconception that two of the three adequately
powered trials of fluoxetine for this indication were positive arises from
ambiguity and error.<3> The one positive trial was of citalopram but
another trial of citalopram was negative.<4> The magnitude of
efficacy in all trials is consistent with our meta-analysis finding of a
mean benefit equivalent to 3-4 points (95% CI 1-8) on the Children’s
Depression Rating Scale (range 17-113).<2> That small benefit is of
dubious clinical importance compared to mean improvements from baseline of
15-25 points in placebo groups.
Based on clinical experience, many clinicians believe that
antidepressant drugs produce worthwhile benefits. When patients improve
after being given a drug they attribute the improvement to the drug.
Aristotle described such thinking as the “after that therefore because of
that” fallacy. Other causes for clinical improvement, that might account
for the large improvements seen in placebo groups, include non-drug
effects of the medical encounter, regression to the mean, improvement that
would have occurred without treatment, faith in pills and getting a reason
for optimism.
1. Geddes JR, Cipriani A. Selective serotonin reuptake inhibitors.
BMJ 2004;329:809-810
2. Hall WD, Mant A, Mitchell PB, Rendle VA, Hickie IB, McManus P.
Association between antidepressant prescribing and suicide in Australia,
1991-2000: trend analysis. BMJ 2003;326: 1008
3. Jureidini JN, Doecke CJ, Mansfield PR, Haby MM, Menkes DB, Tonkin
AL. Efficacy and safety of antidepressants for children and adolescents.
BMJ 2004;328:879-83
4. Laughren T. Slide 13. Regulatory Background on Antidepressants and
Suicidality in Pediatric Patients. Presentation at Joint meeting of the
CDER Psychopharmacologic Drugs Advisory Committee and FDA Pediatric
Advisory Committee, Sept 13-14, 2004
http://www.fda.gov/ohrms/dockets/ac/04/slides/2004-4065S1_02_FDA-
Laughren_files/frame.htm (accessed 8 Oct 2004).
5. March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, et al;
Treatment for Adolescents With Depression Study (TADS) Team. Fluoxetine,
cognitive-behavioral therapy, and their combination for adolescents with
depression: Treatment for Adolescents With Depression Study (TADS)
randomized controlled trial. JAMA. 2004 Aug 18;292(7):807-20.
Competing interests:
None declared
Competing interests: No competing interests
Re: The THREAD trial
Although it is good news that the “THREAD” trial investigates the
additional effectiveness of SSRIs over supportive care, it will not supply
guidance in the antidepressant controversy between psychiatry and general
practice in the Netherlands. The recent Dutch College of GPs’ guideline on
depression adopts a critical attitude towards antidepressants.1 These may
be only slightly more effective than placebos in primary care, especially
for dysthymia and minor depression. Another national guidance body, the
multidisciplinary guideline committee on mood disorders, has also just
issued a (draft) version of its guideline which is more positive about
antidepressants. However, the psychiatrists involved have refused to
discuss what the GPs considered the most important issue: the evidence of
antidepressants versus placebo. Consequently, for the first time in its
history, the Dutch college of GPs has just last month rejected this
guideline.
Although general practitioners (GPs) now prescribe antidepressant
drugs in about 80% of their contacts for depression,2 the evidence base
for antidepressants in primary care is weak. Methodological insights such
as adequate blinding remain seldom used in psychiatric research and
observed effects are small.3 Peveler and Kendrick cite the trial by Judd
et al.4 The design of this study shows various forms of selection bias
such as a lack of independent evaluators and a placebo washout period of
four weeks. Judd et al observed a small and non-significant effect (–0.20;
95% CI: -0.51 to 0.11) on their best-known outcome, the 17 item Hamilton
Depression Rating Scale (HDRS), with a mean HRSD end-score in the
fluoxetine arm of 7.1 and of 8.1 in the placebo arm.
If the evidence that antidepressants have a specific effect against
depression in primary care is so weak, homeopathic drugs may be a better
and cheaper alternative. Perhaps “THREAD” can use those as their
comparison condition.
Reference List
1. Van Marwijk H, Grundmeijer H, Bijl D, Van Gelderen M, De Haan M,
Van Weel-Baumgarten E et al. Dutch College of General Practioners
Guideline Depression, first revision [NHG-Standaard Depressieve stoornis
(depressie). Eerste herziening. In Dutch]. Huisarts Wet 2003;46:614-23.
2. Cardol M, van Dijk L, de Jong J, de Bakker D, Westert G. Second
national study of illnesses and operations in general practice: general
practice care: what does the gatekeeper do? [In Dutch]. Utrecht,Bilthoven:
NIVEL, National Institute of Health and Environment, 2004.
3. Moncrieff J, Wessely S, Hardy R. Active placebos versus antidepressants
for depression. Cochrane.Database.Syst.Rev. 2004;CD003012.
4. Judd LL, Rapaport MH, Yonkers KA, Rush AJ, Frank E, Thase ME et al.
Randomized, placebo-controlled trial of fluoxetine for acute treatment of
minor depressive disorder. Am.J Psychiatry 2004;161:1864-71.
Competing interests:
None declared
Competing interests: No competing interests