Newer antidepressants for the treatment of depression in adultsBMJ 2012; 344 doi: https://doi.org/10.1136/bmj.d8300 (Published 19 January 2012) Cite this as: BMJ 2012;344:d8300
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A large meta-analysis of randomized controlled clinical trials (RCTs) revealed that anti-inflammatory drugs greatly improved depressive symptoms in patients with Major Depressive Disorder (MDD) as add-ons or as monotherapy.
Competing interests: No competing interests
Hatcher and Arroll did not mention enough the relevance of severe adverse drug reactions (ADR) associated with newer antidepressants.
Degner et al.(1) observed in an European Drug Surveillance project an overall incidence of severe ADRs of all antidepressants of 1.4% of exposed psychiatric in-patients. There is an increase of polypharmacy in psychiatric patients. Rüther et al.(2) observed that only 30% of in-patients recieved a single antidepressant.
Different antipychotic groups (SSRI, SNRI vs. tricyclic antidepressants) differed significantly in their ADR profiles. There are relevant ADRs associated with SSRI. The risk of (gastrointestinal) bleedings (3) and of osteoporosis and fractures (especially in older patients)(4). Suicidal behaviour and ideations(5) remain unclear in younger depressed patients and are discussed in public(6). A further problem is a QTc prolongation in treatment with citalopram and escitalopram(7). The extensive use of newer antidepressants in older patients may be a high risk. Good cooperation between general practitioners and psychiatrists is necessary.
1) Degner D, Grohmann R, Kropp S, Rüther E, Bender S, Engel RR, Schmidt LG.Severe adverse drug reactions of antidepressants: results of the German multicenter drug surveillance program AMSP. Pharmacopsychiatry 2004;37 S1:S39-45
2) Rüther, E., Grohmann, R., Degner D, Gruber-Rüther, A., Loosen, P. Drug Surveillance in Psychiatry: Update on Antidepressants. Abstract, ACNP-Meeting, 2007
3) Andrade C, Sandarsh S, Chethan KB, Nagesh KS.Serotonin reuptake inhibitor antidepressants and abnormal bleeding: a review for clinicians and a reconsideration of mechanisms. J Clin Psychiatry 2010;71(12):1565-75
4) Ziere G, Dieleman JP, van der Cammen TJ, Hofman A, Pols HA, Stricker BH.Selective serotonin reuptake inhibiting antidepressants are associated with an increased risk of nonvertebral fractures. J Clin Psychopharmacol. 2008;28(4):411-7
5) Goldsmith L, Moncrieff J.The psychoactive effects of antidepressants and their association with suicidality. Curr Drug Saf. 2011;6(2):115-21
6) Hernandez JF, Mantel-Teeuwisse AK, van Thiel GJ, Belitser SV, Raaijmakers JA, Pieters T.Publication trends in newspapers and scientific journals for SSRIs and suicidality: a systematic longitudinal study. BMJ Open. 2011 Dec 6;1(2):e000290. Print 2011.
7) Howland RH.A critical evaluation of the cardiac toxicity of citalopram: part 1. J Psychosoc Nurs Ment Health Serv. 2011;49(11):13-6
Competing interests: No competing interests
Hatcher and Arroll offer comprehensive advice on prescribing the Newer Antidepressants, which seems to be ever more common.
In my own practice ( a rural Welsh idyll ! ) I was shocked to learn that over 10% of women were taking antidepressants in the last year, and some one-sixth of those had tried 2, 3 or 4 different classes.
Anecdotally, I find that most patients offered antidepressants do not seem to be helped by them. They will often either not take them, or stop them early. Switching drugs is unlikely to help, as evidenced by the numbers switching a second or third time.
Given that antipressants are not addictive, have long half-lives, and are poorly tolerated, what evidence is there for their advice to withdraw slowly , and switch over weeks ?
Why not just chop or change the offending item ?
Competing interests: No competing interests
This series of articles on therapeutics is of great help to practising doctors and of interest to clinical pharmacologists such as myself. However, I am prompted to respond for a number of reasons.
It is surprising for the article to be entitled ‘Newer Antidepressants’, for Fluoxetine was first registered in 1987 and most of the antidepressants covered are now indeed off-patent and available generically. I expected the article to be about drugs such as Agomelatine, which is truly ‘newer’.
It was also surprising to me that the article did not stress that any antidepressant is only part of the management of patients with depression, which should also include one of the many forms of psychotherapy available, self-help in the form of personal development, and probably alternative therapies such as meditation, massage and visualisation. All these help lead to changes in emotions, thought and lifestyle. If prescribed by a doctor insurers such as BUPA, who are very careful with their money, will willingly pay for the alternative therapies in depression.
Antidepressants have to be used in conjunction with frequent visits to a responsible clinician, particularly in the early stages of treatment to detect the possible unhelpful changes in behaviour that these drugs can produce. Carers, spouses, partners, parents and offspring should also be warned to observe for these changes. It does not stress that due to the time these medications take to work, that it is usual that side effects are apparent prior to therapeutic effect and it is often hard to keep patients on the medication as they see more distress than improvement. The early agitation, anxiety and other side effects are minimised by starting in small doses and increasing incrementally.
The side effects may be very distressing, particularly those around behaviour, mood, emotions and feelings, as well as sexual dysfunction. Among medications they are the most troublesome in that they often produce delayed orgasm or even anorgasmia, in addition to loss of libido and erectile dysfunction.
This adverse effect is so marked that those with an interest in sexual health have been using the SSRIs as a treatment for premature ejaculation for many years and in fact one of the newer SSRIs, Dapoxetine (brand mane in the UK, Priligy), has received a marketing authorisation for this condition, although currently I believe is only available on private prescription.
Surprisingly, the article makes little of the controversies surrounding this group of compounds in relation to increases in suicidal thinking and behaviour, as well as other behavioural changes which may precipitate forensically important behaviour such as aggression.
In relation to the former, there is a clear age related effect with a marked excess in those of and below adult age, a significant effect in those aged under 24, with variable and possible neutral effect between 25 and 64, only in those aged over 65 is there a net decrease. In all age groups the net effect is probably due to them decreasing suicidal thought content and behaviour in a significant proportion, while also increasing it in others. It being only the net effect which is different across the age structure.
The absence of any consideration of the controversies surrounding their use is, I believe, a significant omission.
The US full product information labelling and the SPC advise caution and observation of patients starting SSRIs for abnormal behaviour and increasing aggression. Although early work did not clearly show the effect of these medications, many such as Breggin (1) and Healy, Herxheimer & Menkes (2) have raised concerns.
A recent paper by Moore (3) et al entitled ‘Prescription Drugs Associated with Reports of Violence Towards Others’, to my mind clearly shows that there is a high chance that they do produce, as a class, violence towards others, although the standard three-legged defence may still apply in that these events are more common in the patients who have them, there is lack of consistent proof of this effect and that the patients may have other predisposing reasons for this behaviour.
There is no doubt that in some patients they may cause behaviours associated with forensic events from shoplifting to possible homicide, including mania, psychosis, flattened emotions and psychomotor restlessness or akathesia and that if these events occur, then a thorough assessment is called for in each and every case, as detailed in many publications including my own entitled ‘Could the cure really be the cause?’ (4).
The time the patient is most at risk is when the dose is increasing or decreasing, particularly if they get a withdrawal syndrome.
In the other area where caution has to particularly be applied, is in their effects on platelet aggregation and the possibility that they cause a propensity to disorders of haemostasis and bleeding. This is particularly noticeable when other drugs with serotoninergic properties are used with them such as Sumatriptan and similar compounds. There is also the difficulty that some SSRIs like Duloxetine are not only indicated in depression, but also in other conditions whereby people may not immediately consider them to be SSRIs. This will undoubtedly relate to Dapoxetine. They also interact with non steroidal anti inflammatory drugs, steroids, Clopidogrel and Warfarin.
In my extensive experience of SSRIs gained from coordinating the clinical development of them; being a hands on psychiatric investigator, a practising physician with an interest in mental health, coordinator of parental support groups in an adolescent and young adult mental health unit, it is by no means unusual for patients, or those associated with them, to phone in distress with side effects, even though they may be absent or minimal in half the patients taking them. Sleeplessness and disturbance of sleep architecture is often a problem and although the authors recommend short term benzodiazepines for this, I have seen many patients in who this is impossible to stop due to both withdrawal symptoms and severe insomnia and many end up addicted. Alternatively, I have found more benefits from using a nocturnal dose of Trazodone.
The other experience I have is as a patient, and I have experienced Fluoxetine induced severe insomnia, sexual difficulties with Paroxetine, severe psychomotor restlessness after a single dose of Venlafaxine and Reboxetine associated mania. Luckily I have remained well for many years.
I have also worked extensively with cardiovascular drugs such as antiarrhythmic agents post myocardial infarction and despite the medical complexities and dangers with these compounds, they have caused me nowhere near the difficulties of SSRIs. Despite these difficulties, the SSRIs have been a very useful addition to the treatment of depression and although the authors should be commended on getting so much information into six pages, I have some regrets that they do not spend more time talking about the difficulties they may cause to patients and those prescribing.
Dr Malcolm VandenBurg BSc MBBS FISMA FCP FFPM FRCP
T: 07850 049 134
(1) Peter R Breggin. Suicidality, violence and mania caused by selective serotonin reuptake inhibitors (SSRIs): A review and analysis. International Journal of Risk and Safety in Medicine 16 (2003/2004) 31-49.
(2) David Healy, Andrew Herxheimer, David B Menkes. Antidepressants and Violence: Problems at the Interface of Medicine and Law. PLoS Medicine. September 2006: volume 3: issue 9: e372.
(3) Thomas J Moore, Joseph Glenmullen, Curt D Furberg. Prescription Drugs Associated with Reports of Violence Towards Others. PLoS One. December 2010: volume 5: issue 12: e15337.
(4) Malcolm VandenBurg. Could the cure really be the cause?’ Your Witness. Summer 2009. A Press Publishers Ltd. Stockport UK.
Competing interests: Malcolm VandenBurg has given expert opinions to the courts in many legal cases were SSRIs have allegedly been implicated, in criminal, civil and family courts. Malcolm VandenBurg worked in the pharmaceutical industry for over 25 years and now has a private practice integrating the care of patients with mental health issues.
The article mentions that ""there is some debate about" the efficacy of
SSRIs and that authors often declare "significant competing interests".
Nevertheless the BMJ is publishing again an article about SSRIs (following
on from http://www.bmj.com/content/343/bmj.d5219 ). This time it is not a
"Clinical review" but under the headings (established?) "Practice" and
I like to invite research professor David Colquhoun and professor Edzard
Ernst to comment on the safety and efficacy of SSRIs compared with
homeopathic remedies. Especially prof Colquhoun should step up rather than "won't
go into depression, because that is the subject of disgraceful fraud by the
pharmaceutical industry. It is (or should be) a matter for the police not
Professor Ernst would be able to comment on issues in the article such as
"reinforces the need to add in psychological therapies", "the need for
non-drug treatment" and furthermore the placebo effect.
Both can employ their expertise and compare the billions spend on SSRIs and
the million on homeopathic remedies for the same indications and compare the
safety profile and deaths as a result of taking SSRIs as compared with the
"A to Z of the well being industry"
http://www.bmj.com/content/342/bmj.d2711 and to find out whether
the cheat, trick or treat is cheaper, safer and more graceful.
Competing interests: I am skeptical about SSRIs and homeopathy (particulary when the latter is more diluted than pheromones).
The article only quotes prescribing data to 2005 and suggests that the increase is due to long treatment of patients. But the data from 2005 shows a massive and increasing 40% in SSRI antidepressant prescriptions, a rate that surely must in part reflect an increase in depression diagnosis.  Accurate data from the UK is hard to find, but certainly in the USA ,our mental weather vane, the reported incidence of major depression doubled in a decade from 1992 to 2002.  Anecdote would suggest depression diagnosis has increased in the UK .
But even if as we genuinely believe the rapid increase is merely down to longer prescriptions, do we have long term data of efficacy and safety? 40 million prescriptions annually are incredible numbers, is this really good medicine ? Can we really defeat depression through medication? Indeed there other absolutely fundamental issues. Are antidepressants much better than placebo? Research suggests not [3,4]. Has the evidence base been distorted for profit? Research suggests so.  Do we know the long term benefits of antidepressants and safety? There is much more to this than these antidepressant guidelines suggest.
Competing interests: No competing interests