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Mental health conditions

Why antidepressants are still the best treatment for depression

A recent meta-analysis by Andrea Cipriani and colleagues from the Department of Psychiatry at the University of Oxford concluded that antidepressants do not have a clear advantage for childhood and adolescent depression[1] . The research received much media attention and was used as another opportunity to discredit antidepressant medicines. However, much of the media coverage ignored the fact that the paper did not actually show that antidepressants do not work in this age group, just that the evidence was of such low quality that a conclusion of efficacy could not be made[2]. The uncritical promotion of psychological therapies as the obvious safe and effective alternative to antidepressants was concerning. Even the comment piece in The Lancet assumed that “evidence-based psychotherapy” was the obvious alternative[3].

There has been huge growth in psychological therapies in the UK, with Improving Access to Psychological Therapies — an NHS England initiative that aims to increase access to psychological treatments — receiving £118m annually from 2012 to 2019 to increase services. This investment has partly been fuelled by uncritical reinforcement of the view voiced by clinicians and the media that psychological therapies are a safe and effective alternative to antidepressants[4]. This viewpoint needs to be challenged because the evidence base for psychological therapies is nowhere near as robust as many health professionals assume.

Flawed research methods

Consider this scenario: in response to the need for an effective and safe alternative drug treatment for depression, my pharmacist colleagues and I have developed a therapy called ENC. We have carried out a trial to prove its effectiveness which involved handpicking English-speaking patients and splitting them into two groups. We engaged with the first group (ENC group), took an interest in their problems and talked to them. The other group were told that we knew they were depressed but we were not going to treat them and instead put them on a 16-week waiting list. After 16 weeks, those in the ENC group were much better than those in the group we abandoned. We know the treatment is safe and does not have any side effects, so we did not ask the patients whether or not they had experienced any.

Would the scientist in you take this seriously? Of course not. It was not randomised, not double blind, there was no matched placebo or equivalent control group. It was carried out in an expert centre with handpicked, English-speaking patients and there was no systematic investigation of adverse effects. The analysis was of study completers rather than intention-to-treat, inflating its apparent effectiveness by ignoring dropouts, which would not satisfy any regulator worldwide were this a drug treatment. The trial did not have to be registered anywhere in advance so, if it failed, it probably would not have been published. Plus a waiting list control of 16 weeks would lead to eventual treatment starting much later, something that is, arguably, unethical.

Sadly, this scenario is not as far-fetched as you might think – it is indicative of the quality of the evidence for the efficacy of psychological therapies in depression, a potentially life-threatening, recurrent and highly distressing condition, with numerous and serious risks to the individual and others. These include harm to relationships, a risk of suicide, cognitive impairment[5], hippocampal atrophy[6], substance misuse and a 2.5 times increased risk of dying early[7].

Trial design flaws

Rather like the ENC trial, one of the big problems with the evidence base for psychological therapies is trial design. The use of waiting lists as a control group should be open to criticism.

Patients are divided into two groups. Giving one group the intervention while the other is put on a waiting list is clearly an open trial strategy. It does not compare a treatment with a matched or equivalent control. In medicine trials, such a design would not be credible and would probably be considered unethical. The 2010 National Institute for Health and Care Excellence guidance on depression[8] defends waiting lists as a valid trial design by noting a review (19 studies, 221 patients) in which 20% of people improved within 4–8 weeks and 50% improved within 6 months while on a waiting list[9]. However, a much larger network meta-analysis (49 studies, n=2730) showed that someone was nearly three times more likely to respond to “no treatment” than being on a “waiting list”[10]. So, in fact, doing nothing is better than being put on a waiting list. It is hard to see how psychologists can defend testing their treatments against a waiting list control. Also, one might wonder how effective antidepressants would be in trials if compared with a waiting list rather than in a randomised double-blind comparison with a matched placebo.

There is evidence of publication bias for psychological therapies, with effect sizes higher than expected overall and much higher in smaller or low quality studies[11],[12]. This has also been identified in some pharma-led depression trials. Study validity assumes that psychological therapies carried out in a local area are as effective as those carried out by specialists at expert centres. We also do not know if they would work with people of different cultures, who may not speak English fluently and who may have less capacity to cope with the therapy.

Adverse effects

Like medicines, psychological therapies carry adverse effects. For example, quoting from a psychotherapy study in depressed adolescents, “emergent suicidality is a common occurrence in psychosocial treatment of adolescent depression, with rates similar to those reported recently in antidepressant trials”[13]. In this trial, suicidal ideation was 12.5% (one in eight patients). This may not be a representative estimate but, unusually, adverse effects were specifically measured and reported in this study. Suicidal ideation has been reported to be higher with antidepressants than with psychological therapies (18.6% versus 5.4%) based on limited evidence[14], although this seems age-related, with the risk dropping as age increases past adolescence[15].

Other adverse effects of psychological therapies can include withdrawal reactions (e.g. distress) on abrupt discontinuation or completion of sessions.

Another possible “adverse effect” is the withholding of other treatments, such as antidepressants in adolescent depression. I vividly recall running a group session in Norfolk for parents of adolescents with mental health problems. The mother of a 17-year-old with depression said her daughter “had tried cognitive behavioural therapy and that made her worse, but the GP will not prescribe antidepressants until she is 18, and now all I’m trying to do is keep her alive until she gets to 18 so she can be treated properly.” This was not an isolated remark.

Strong evidence

Antidepressants are effective regardless of a patient’s language, IQ, race, background, personal relationships, and the quality of the therapist and the prescriber. They start to work in four hours[16],[17], there are no waiting lists or restrictive criteria for acceptance for treatment, and they can start to work even when the individual is too depressed to engage with any type of therapy. Antidepressants reduce the risk of suicide in adults[18], but in adolescents the rate of suicidal ideation is slightly higher[15]. In terms of numbers needed to treat (NNT), the evidence base for relapse prevention is 3.5 (P<0.00001)[19], one of the strongest effects in medicine. In comparison, statins have an NNT of 30.

Many registration trials of antidepressants over 4–8 weeks still show efficacy over placebo, which is remarkable considering placebo response has been increasing steadily over the past few decades. Placebo is often equated with nothing, but this is wrong, nor is it no treatment or a waiting list. In a placebo-controlled trial, the patient and prescriber know the patient might be having an active treatment (a 50% chance if there are just two arms, 66% if there are two active arms). Comparing two active treatments (with no placebo arm) produces a mean 13% (65% versus 58%) higher response than the response to an antidepressant versus placebo, because both groups of participants know they are receiving an active treatment[20]. But the doubt also adds uncertainty and may level-out the response to placebo and active intervention. More frequent assessments inflate the placebo response. Trial differences also assume that everyone responding to placebo would also have responded to an antidepressant, which, if not true, would further separate the drug-placebo response. In a condition where hopelessness can be a prominent symptom, any treatment is enormously reassuring and can lead to some short term improvement, but placebo response does not generally show an enduring response. The fact that antidepressants can show efficacy in the relatively short term (4–8 weeks) and in the long term (years) against placebo is indicative of how effective they are.

Not perfect

There is no doubt that there are dangers associated with antidepressant use so they must be used carefully, such as starting on a low dose, increase the dose slowly to avoid any heightened anxiety, and monitor carefully for treatment-emergent akathisia — a movement disorder characterised by a feeling of inner restlessness and a compelling need to be in constant motion — because this has been linked with suicidal ideation[21].

This is also not to say that psychological therapies do not work for depression at all. They benefit some people, but they are not a universal panacea. Some may find that antidepressants work, others prefer therapy, and other people favour a combination of both. But one thing is clear: the evidence base for antidepressants is much stronger than for psychotherapy.

The reality is that, with both treatments, we have not worked out how to assess the effects fully. But robust randomised, properly controlled trials with minimal exclusions need to be conducted to assess the effectiveness of psychological therapies before pharmacists and other healthcare professionals can recommend them over antidepressants.

As an example, I was acting as the external assessor for a chief pharmacist interview in 2015 and asked each of the candidates which drugs they would select should the world only be able to afford the resources for five medicines for the whole of mental health. One candidate listed three antipsychotics and then stated: “Well, we don’t need antidepressants”. When I asked why my depression doesn’t need treating, the candidate dismissively stated: “Well, you can have psychotherapy”. It was worrying that someone already in a senior position in mental health could be so ill informed.

Antidepressants are still the most effective treatment we have for depression and studies such as the one conducted by Cipriani et al[1] probably underestimate their effects. Depression is dangerous and harmful to the brain and antidepressants significantly reduce relapse if taken long term. There are no studies of psychological therapies for depression that would be robust enough to allow licensing were the intervention a drug therapy[22]. We should not allow the media to dismiss antidepressants based on poor quality evidence, nor indeed uncritically promote psychological therapies based on inadequate evidence. If we do we could be looking at the Emperor’s New Clothes here. Or ENC, as we called it.

Stephen Bazire BPharm, FRPharmS, FCMHP, MBE, Honorary Professor, School of Pharmacy, University of East Anglia, Norwich; Director Mistura Enterprise (trading as Choice and Medication) and Mistura Informatics, Trustee, Norwich and Central Norfolk Mind. Correspondence to: steve.bazire@misturainformatics.org 

Citation: Clinical Pharmacist DOI: 10.1211/CP.2016.20201413

Readers' comments (4)

  • Very interesting perspective, however even NICE guidance suggests that in mild depression antidepressants are not effective and promote healthy living strategies with or without talking therapies as first-line treatment. Now this might be because people have to be really quite severely depressed to respond to an antidepressant.
    I think it is a little disingenuous to state that antidepressants start working within 4 hours as suggested by references 16 and 17. They do not start working; they start affecting neuroreceptor modulation. These two studies also took place in healthy volunteers so the effect in people with depression cannot be translated from these results.
    What we do know is that there are risks associated with talking therapies and with medication and the individual needs to be fully informed on both sides of the choice before they can make an informed choice.
    Denise Taylor

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  • Andrew Low

    This is an interesting article on a mental health theme,an often forgotten area.Having schizophrenia and having had episodes of depression,I do believe antidepressants work and take the edge off the suffering.I put on weight with mirtazapine.Sertraline my GP described as "the least of these devils".
    Sahaja Yoga meditation is a lifeline for me,and now there is randomised placebo-controlled trial evidence.Read "Silence Your Mind"(2014) by Dr Ramesh Manocha,GP and researcher at the university of Sydney in Australia.The author makes the point that if there is mental illness there should be supervision by a mental health professional.Those are not generally available so it is important that more is done to promote Sahaja Yoga.We need more Sahaja Yogis!
    My perception is that Stephen Bazire and pharmacist colleagues do not think highly of psychological therapies,calling them "the Emperor's New Clothes" or ENC,after the story by Hans Christian Andersen.This has connotations of vanity and not listening and nakedness and basically not being able to run a bath.The gloves are off and it is a bare knuckle fight.Certainly I find this with psychiatry.To be fair,the guru of Sahaja Yoga,Shri Mataji Nirmala Devi also said that She thought psychologists couldn't do much.I feel that mental health professionals do need to be more honest and kinder.They need to "cough up".About vulnerability to coughing or the sound of traffic in my schizophrenia or guilt related depression they need to say that coughing can be "most malicious" (Dickens) or "contemptuous" (Chekhov).It can be said that a collective crime against humanity is being committed by silence about things like what Carl Jung called the (painful) birth of collective consciousness.There is a silence about Sahaja Yoga.
    There is too much hiding behind the prescription pad and the role of the medication and not nearly enough honesty or candour.There is such a thing as a duty of candour too.

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  • Thanks Denise, and I know what you're trying to get at. However, having been on a NICE GDG and read many of the other related ones just because NICE says something it doesn't mean it is correct or even backed with any data e.g. the Bipolar guidelines decided that lithium only needs to be monitored every 6 months. Even the full-length version gave absolutely NO justification or reason for this whatsoever (other than informally that it never gets done properly so why bother) despite there being evidence that even a single toxic/high level can damage the kidneys and that can be detected for months afterwards. So monitoring every 6 months (whichg practically means every 9 months) gives a full 6 extra months at a potentially toxic lithium level and damaged kidneys. Then lithium gets the blame!
    References 16 and 17 used response to fearful facial expressions to detect a change in depressive thinking so it is not disingenuous to say that antidepressants start working after 4 hours as it wasn't neurotransmitter changes that were being measured but the changes in negative thinking.
    The point I was trying to make throughout Denise and Andrew was that it's the EVIDENCE that is the problem, and this may have got lost in the editing. There should be equivalent standards for studies, not one strict set of rules for one and much softer rules for another. And because people like NICE consider the evidence equally robust other people will take that at face value.

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  • An extremely well written and thought-provoking article. You make a good point by saying that we can't really compare drug trials and psychotherapy trials fairly.

    Regarding NICE guidelines, it's important to remember that NICE don't just focus on the efficacy of treatment options, but also the cost-effectiveness. Presently, the guidelines state that antidepressants should not be used for mild depression, not because they would not work, but because research has shown that it is not good value for money to do so (£/QUALY).

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