Long term treatment of depression with selective serotonin reuptake inhibitors and newer antidepressants
BMJ 2010; 340 doi: https://doi.org/10.1136/bmj.c1468 (Published 26 March 2010) Cite this as: BMJ 2010;340:c1468All rapid responses
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David Evans points out correctly that there were SSRIs available
before the arrival of fluoxetine. Zimeldine was withdrawn due to an
association with Guillain-Barre syndrome, indalpine was withdrawn due to
an association with neutropenia and fluvoxamine had nowhere near the
impact of fluoxetine (Prozac), not only on antidepressant prescribing but
also on late 20th century culture.
As stated in the table itself the data in Table 2 are taken from a
meta-analysis that attempts to quantify rates of treatment-emergent sexual
dysfunction as compared to placebo. The important point is the high
prevalence of sexual dysfunction (albeit self-reported) associated with
most antidepressants but particularly those that are commonly prescribed,
a problem that often passes with no acknowledgement.
Competing interests:
None declared
Competing interests: No competing interests
1.
This article starts by implying that fluoxetine was the first SSRI in
clinical use. This isn't true. Here in the UK fluvoxamine was the first to
be marketed and fluoxetine came along two years later. In the US I think
the first SSRI launched was a drug called zimelidine, later withdrawn on
safety grounds.
2.
Later there is table quoting rates of sexual dysfunction with different
antidepressants. Apparently escitalopram causes half as much sexual
dysfunction as citalopram, which is very improbable considering that they
are essentially the same drug. I do not have access to the full text of
the review article referenced. Would I be right in suspecting that these
confidently quoted figures come from separate studies, rather than direct
comparisons of the drugs? Sexual dysfunction is such a subjective thing
that surely anything less than a head-to-head comparison should be
regarded as very dubious?
Competing interests:
None declared
Competing interests: No competing interests
I read Steven Reid's and Corrado Barbui's "Long term treatment of
depression with selective serotonin reuptake inhibitors and newer
antidepressants" BMJ 2010; 340: c1468 with great interest. I am impressed
with the comprehensiveness of the review however I also would have liked
to find comments regarding postnatal mental health care, in particular
safety in the case of breastfeeding.
Competing interests:
None declared
Competing interests: No competing interests
All clinical research has limitations and as such evidence will
rarely be without flaws. Antidepressant trials are a clear example, indeed
exemplar, of this: the problems of short term follow-up, mixed populations
and selective publication have been well rehearsed elsewhere. Yet the
randomized evidence we have reviewed is the best evidence that has been
produced on the long term treatment of depression with antidepressants. In
this scenario, we may either make the best use of the available evidence
or we essentially ignore it. Spence dismisses one meta-analysis that
despite its limitations found a consistent treatment effect across 31
trials (including 4410 patients) and ignores the more recent reviews that
focus on newer antidepressants. We believe that it is more helpful to
produce guidance based on the available evidence than to have no guidance
at all. Continuing antidepressant treatment roughly halves the absolute
risk of relapse, and the benefit of continuing antidepressant treatment is
seen even when discontinuation trials are excluded from re-analyses - is
an NNT of 4-5 really so paltry? We would certainly, as noted in our
conclusion, agree that there is need for further and better research into
the benefits of SSRIs and other antidepressants in the long term. In the
meantime, we believe that the advantages of continuing treatment for 12
months after recovery should not be ignored.
The widespread use of SSRIs, particularly in mild to moderate
depression, is an important issue, but the purpose of our review was to
examine the evidence around length of therapy for individuals who have
responded to antidepressants, rather than who should be started on such
treatment. If a patient has received no benefit from an antidepressant
there would seem little justification in continuing it in the long term.
Competing interests:
None declared
Competing interests: No competing interests
The authors Reid and Barbui(1), have given a good explanation of the
need to limit the long-term use of antidepressants to one year after
recovery and consider longer term treatment for those who have risk
factors for relapse or have had several episodes of depression due to the
various side-effects of the SSRIs and newer antidepressants. They have
stressed the importance of regular reviews and gradual discontinuation of
the drugs, following recovery. However, in practice a large number of
people remain on antidepressants for a number of years. This may be
because co-morbid conditions such as substance misuse(2),(3) are under
diagnosed or not managed effectively, perhaps due to a lack of insight on
the part of the patient, creating a perception that recovery from
depression is partial or incomplete. Additionally, comorbid conditions to
consider are other mental disorders(4), physical health conditions such as
pain(5) and social problems(6).
The prescription of antidepressants has increased since the
availability of selective serotonin receptor inhibitors (SSRIs)
antidepressants. The cost of lost revenue due to absenteeism at work due
to depression is substantial and General Practitioners are expected to
treat depression effectively to reduce the burden in society(7),(8). This
is a topical issue at a time when the heavily indebted UK government
cannot be generous with extra benefits.
NICE recommends that antidepressants should be avoided in mild
depression. Antidepressants should be used for moderate to severe
depression and continued for 6 months after recovery to reduce the risks
of relapse(9). However, a large study by Moore et al(10) reported that
79.4% of 189851 people in the USA who had been diagnosed with first
episode depression were treated with antidepressants. This suggests that
those with mild depression were also treated with antidepressants,
possibly reflecting the practice in the private sector.
Antidepressants are usually initiated in primary care. The system of
referrals from primary to secondary care varies in different countries and
studies from one country may not easily be extrapolated to another
country. As a result, there is an inconsistency in treatment plans, as
highlighted above.
Large studies to include the management of every episode of
depression, including the name of the drug prescribed, the length of
treatment, the origin of the prescription (primary or secondary care), and
the reason for discontinuation, over a reasonably long period, possibly
the previous 10 years would help to identify the pros and cons of
antidepressants and make recommendations for future management. This is an
essential area of research that may come some way towards resolving the
ambiguity over current management plans, in particular the administration
of medication and length of treatment for clinical depression.
References:
1. Steven Reid and Corrado Barbui. Clinical review: Long term
treatment of depression with selective serotonin reuptake inhibitors and
newer antidepressants. BMJ 2010;340:c1468
2. Davis L, Uezato A, Newell JM, Frazier E. Major depression and
comorbid substance use disorders. Curr opin Psychiatry. 2008 Jan;21(1): 14
-8
3. Han B, Gfroerer JC, Colliver JD. Associations between duration of
illicit drug use and health conditions: results from the 2005-2007
national surveys on drug use and health. Ann Epidemiol. 2010 April;20(4):
289-97. Epub 2010 Feb 19.
4. Möller HJ. Anxiety associated with comorbid depression. J Clin
Psychiatry. 2002;63 Suppl 14: 22-6
5. Kirsh KL. Differentiating and managing common psychiatric
comorbidities seen in chronic pain patients. J Pain Palliat Care
Pharmacother. 2010Mar;24(1): 39-47
6. Aneshensel CS. Towards explaining mental health disparities. J
Health Soc Behav. 2009 Dec; 50(4): 377-94
7. Hilton MF, Scuffham PA, Vecchio N, Whiteford HA. Using the
interaction of mental health symptoms and treatment status to estimate
lost employee productivity. Aust NZ J Psychiatry 2010 Feb; 44(2): 151-61
8. Birnbaum HG, Kessler RC, Kelly D, Ben-Hamadi R, Joish VN,
Greenberg PE. Employer burden of mild, moderate and severe major
depressive disorder: mental health services utilization and costs, and
work performance. Depress Anxiety. 2010; 27(1): 78-89
9. National Institute for Health and Clinical Excellence. Depression:
the treatment and management of depression in adults (partial update of
NICE clinical guideline 23). October 2009. Clinical Guideline 90. 2004.
http://guidance.nice.org.uk/CG90/NICEGuidance/pdf/English
10. Moore M, Yuen HM, Dunn N, Mullee MA, Maskell J, Kendrick T.
Explaining the rise in antidepressant prescribing: a descriptive study
using the general practice research database. BMJ 2009; 339:b3999.
Competing interests:
None declared
Competing interests: No competing interests
Reid and Barbui's review on treatment of depression seems
comprehensive and practical. It fails to mention however that the evidence
supporting several of the drugs they quote is strongly biased towards
selective publication of studies showing positive results (1). The fact
that studies that fail to show benefit are not accounted for unavoidably
skews the risk-benefit ratio of these medications and can lead to
inappropiate prescription. This problem has not escaped the attention of
the lay press (2) and we hope it may soon be solved by mandatory
registration of studies at their inception (3). The authors also report
from a recent meta-analysis that " ... the magnitude of the benefit
increases with the severity of depression ... "(4) . This is formally
correct, and the benefit for patients with severe depression is indeed
proven to be significant. Most of the patients with depressions seen
outside a psychiatric setting,however, are likely to suffer with a less
severe form of the disease. From this perspective, BMJ readers would have
been better informed if Reid and Barbui had reported the conclusions of
the authors of the meta-analysis in their entirety, namely that " ... the
magnitude of the benefit of antidepressants compared to placebo may be
minimal or non-existent, on average, in patients with mild or moderate
symptoms" (3).
(1) Turner EH, Matthews AM et al. Selective publication of
antidepressant trials and its influence on apparent efficacy. NEJM 2008
vol. 358 : 252-260.
(2) "Drug giants warned : tell the truth on medicines". The
Independent, 27 February 2008.
(3) Wood AJ. progress and deficiencies in the registration of
clinical trials. NEJM 2009 vol. 360 : 824.
(4) Fournier JC, De Rubeis RJ et al. Antidepressant drug effects and
depression severity : a patient level meta-analysis. JAMA 2010 vol. 303 :
47-53
Competing interests:
None declared
Competing interests: No competing interests
I am grateful that the issue of long term SSRI has been
raised but I have number of reservations. The review
offered on prevention of relapse is published in the lancet
in 2002 [1] this includes a large number of studies, but
these are old ( the earliest 1973) , small ( some only
with 12 patients ) , mixed medications, hospital based and
researched only treatment responders . The total numbers
followed up on treatment from 1 to 3 years is tiny, less
than 500 patients ( indeed only a few hundred on SSRIs) .
The NNT are 4-5 which still means that 70-80% gain no
benefit. Also most studies specifically looking at SSRI
are short lasting less than 1 year.[2] Lastly, this review
is plagued by the usual problems of evidence based
medicine – a poverty of proper epidemiological data on the
natural history of conditions , commissioning bias ,
publication bias and lack of trial registration in previous
decades.
There are 16 million SSRI prescriptions in the UK in primary
care. The real issue is decades of medication and the
endemic use of SSRIs in mild to moderate Depression. I
regret that the conclusions from this review offer little
comfort, reassurance and generalisability to the millions of
current long term users in the UK. There is need for new
research into the benefit and possible complications SSRI
over the long term.
[1] Geddes JR, Carney SM, Davies C, Furukawa TA, Kupfer DJ,
Frank E, et al. Relapse prevention with antidepressant drug
treatment in depressive disorders: a systematic review.
Lancet 2003;361:653-61
[2] Deshauer D, Moher D, Fergusson D, Moher E, Sampson M,
Grimshaw J. Selective serotonin reuptake inhibitors for
unipolar depression: a systematic review of classic long-
term randomized controlled trials.CMAJ 2008;178:1293-301
Competing interests:
None declared
Competing interests: No competing interests
Re: Long term treatment of depression with selective serotonin reuptake inhibitors and newer antidepressants
I am convinced from my own experience and from conversations with others that suppressed anger is in most cases the root cause of clinical depression, which is so common in our society today, also that such anger tends to deepen and harden over the years, which I suggest is why a serious relapse becomes more and more likely the longer the source of the anger remains unaddressed. I may be stating what is already obvious to many counsellors and medical practitioners, who know that a period of counselling often exposes the source of the anger, just as it did with me. But counselling, of course, does not always cure the problem, which requires an act of forgiveness before the anger inside can be removed for ever. In my case, the ninth step of Alcoholics Anonymous, known as the ‘amends’ step, came to my rescue. I wrote a brief letter to my deceased father, whom I had hated since early childhood, which went as follows: “Dear Dad, I’m sorry I always blamed you for everything that went wrong in my life and I hope you are happy and well in Heaven.”
It may defy belief, but in that moment I felt a huge burden was lifted. My anger evaporated. I felt re-born and since that time there has been no sign of the depression which previously blighted my life, nor any further need for treatment with anti-depressants in the years which followed. Counselling was part of my cure, but forgiving the past was all-important in bringing about a full and successful recovery from what was in essence a spiritual illness. It is one thing to recognise the anger within, quite another to remove it entirely, and I would recommend the programme of Alcoholics Anonymous to anyone who suffers with serious emotional problems – not just to problem drinkers, who also frequently harbour long-standing resentments inside.
Competing interests: No competing interests