The elves have blogged about a wide range of research on antidepressants over the last few years. As prescription rates have increased (almost doubled in the last decade), the debate about overprescribing has become more contested.
The huge network meta-analysis by Cipriani et al (2018) presented the best available evidence to date about the efficacy and safety of antidepressants for adult depression. This review concluded that “all antidepressants were more efficacious than placebo in adults with major depressive disorder”. However, the review did not cover specific adverse events, withdrawal symptoms, or antidepressants used in combination with other non-drug treatments. Furthermore, as the included trials were short (8 weeks) and some antidepressant side effects occur over a prolonged period, these positive results should be interpreted with caution.
This same group of researchers have now followed up this work with another systematic review of studies of antidepressant efficacy and tolerability in patients with major depression (Furukawa et al, 2019). This time they focused on finding the optimal target dose of different antidepressants.
According to NHS Digital data (2019), prescriptions of antidepressants have almost doubled in the last decade, which has fuelled heated debate about the overprescribing of antidepressants.
Methods
This is a systematic review and dose-response meta-analysis of double-blind, randomised controlled trials that examined fixed doses of five SSRIs (selective serotonin reuptake inhibitors) (citalopram, escitalopram, fluoxetine, paroxetine, and sertraline) and two other drugs (venlafaxine and mirtazapine) in the acute treatment of adults (aged 18 years or older) with major depression.
They conducted a really comprehensive search of electronic databases (Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS, MEDLINE, PsycINFO, AMED, PSYNDEX) websites of drug licensing agencies and pharmaceutical companies, and trial registries. They did not exclude Non-English papers, and updated their search until 8 Jan 2016.
Doses of SSRIs were converted to fluoxetine equivalents.
They excluded trials of antidepressants for patients with depression and other serious physical illnesses.
They used a random-effects, dose-response meta-analysis model with flexible splines for SSRIs, venlafaxine, and mirtazapine.
The review was funded by the Japan Society for the Promotion of Science, Swiss National Science Foundation, and National Institute for Health Research.
Results
Effectiveness was measured an average of 8 weeks after commencing treatment and defined by a response of 50% or more reduction on an observer-rated scale of depression.
For treatment response, the authors prioritised the Hamilton Depression Rating Scale then the Montgomery-Åsberg Depression Rating Scale, and if neither was used, any other validated observer-rating scale. When treatment response was not reported as an outcome, they calculated response using a validated imputation method.
Dropouts were due to adverse effects (as an index of treatment tolerability), and all-cause dropouts (interpreted as an overall index of treatment acceptability).
Conclusions
Up to an SSRI equivalent 20-40mg of Fluoxetine, 30mg of Mirtazepine or 150mg Venlafaxine, antidepressants are generally effective and tolerated, but effectiveness and tolerability both drop off quite abruptly at higher doses.
The reviewers interpret these findings by saying:
For the most commonly used second-generation antidepressants, the lower range of the licensed dose achieves the optimal balance between efficacy, tolerability, and acceptability in the acute treatment of major depression.
This well-conducted review questions the value of prescribing higher doses of antidepressants for adults with depression.
Strengths and limitations
This is a well-designed and thorough review that answers questions that are relevant to patients and clinicians.
The patients are not representative of patients that we see in general practice:
- Their symptoms are more severe, but their situation is less complex.
- Little is known about their social status or ethnic diversity.
- The average duration of treatment (8 weeks) is far shorter than the recommended 6 months
- The outcome (a reduction in depression rating scores) doesn’t represent the discursive, deliberative informal ways we assess progress. Patients choose to continue their antidepressants because their sleep is a little better, they’ve lost the sharp edges off their anxiety or they feel less irritable (for example), even if there is little noticeable change in their depression.
As always, there is a challenge for evidence producers to conduct research that is applicable to patients in the real world.
Implications for practice
Most antidepressant prescribing happens in primary care: GPs start them, stop them, change doses and change drugs. Access to primary care may not be as good as patients (or many GPs) would like, but it is faster and easier than access to specialist services, and most importantly it is unconditional, local and quite frequently involves relational continuity.
Patients in this study were not representative of the patients that GPs see. It is rare for GPs to see patients for whom depression is the main or only diagnosis. Our patients with severe depression are very often also suffering from anxiety and panic, chronic pain and fatigue and other chronic diseases related to deprivation and self-neglect. A patient who ‘only’ has severe depression is unusual. It is also unusual for a GP to make a diagnosis of ‘major depression’ – I can bring patients to mind who probably did have isolated ‘acute major depression’ like the patients in this paper, but I have never checked off criteria to say that is what they were suffering. They are patients that I worry about, who have all but stopped eating, talking and engaging with the world around them. They are often bought in by a worried friend. They usually look physically sick; bio-psycho-socially withdrawn. They, and those close to them are usually desperate for anything that might help, including and especially medication. But this is not the case for most people that I see with depression, whose symptoms are chronic and enduring and compounded by childhood trauma, social insecurity, chronic pain and disability, who have a long past history of unsatisfactory treatment experiences.
Most antidepressants are prescribed to patients with messy, traumatic histories. Too much medical research suffers from the problem that the patients studied are carefully selected to exclude those with messy, complex histories. And therein lies another issue. Faced with a patient suffering from symptoms of depression and adverse social circumstances, we try to help the person and treating their depression might only be a part of what we offer. We look for social and psychological interventions alongside any prescribing we might do, and helping someone with a successful benefits appeal, or into secure housing or out of a violent relationship might be our most effective therapeutic intervention.
Helping someone with a successful benefits appeal, or into secure housing or out of a violent relationship might be our most effective therapeutic intervention.
These issues aside, it has been my practice for the last couple of years at least to review patients 2-3 weeks after initiating antidepressants and then change or stop them if they are either not tolerated or not working. This is practice based on local expert opinion, not published research evidence. GPs rarely have time to read medical journals except perhaps for skimming the British Medical Journal or British Journal of General Practice. Most of what comes to us is cascaded from local specialists, online guidelines or trusted colleagues. Our days are too long and the work is too intense to critically appraise papers like this. One psychiatrist I know sees up to seven patients a day, I quite frequently have to see or speak to over 40 patients a day.
What I will take from this paper is that if antidepressants are not working at modest doses, then before suggesting an increase in dose I should let patients know that higher doses are rarely tolerated or effective. And the decision will be shared with my patients as it always is (or ought to be).
Prescribers! Do you review your patients 2-3 weeks after initiating antidepressants and then change or stop them if they are either not tolerated or not working?
Neither doctors or patients are rational decision makers. We are also subject to psychological biases. Especially when we are desperate for things to get better, we may be tempted to go for interventions with even the slightest chance of benefit and overlook or downplay the possible risks. Expectations affect outcomes so there is a lot of wishful thinking and optimistic framing, because the evidence is that even with placebos, if we emphasise potential benefits (the placebo effect) they are more likely to help, and if we emphasise adverse effects, they are more frequently experienced (the nocebo effect). Faced with a depressed patient, an indeterminate wait for therapy and little hope of an end to austerity, both patients and clinicians may be tempted to increase the dose of antidepressant whatever the conclusions of this study.
That said, I think I will be less likely to recommend higher doses of antidepressants in future, but this will mean fewer occasions when I can ‘do something’, make a change and wait for something to happen. Instead I am left with more emotional labour: more bearing witness to suffering, more time sitting with patients who are suffering with little to offer except validation, kindness and presence. Other GPs cannot, do not or will not offer continuity or commitment. When looking at studies, what does ‘usual care’ mean? Is this ‘unusual care’? I escalate the dose of the ‘doctor as therapeutic agent’, but how long until the supplies run out?
This evidence suggests that escalating the dose of antidepressant may not be helpful, so instead GPs will have to escalate the dose of the ‘doctor as therapeutic agent’, but how long until the supplies run out?
Conflicts of interest
None.
Links
Primary paper
Furukawa TA, Cipriani A, Cowen PJ, Leucht S, Egger M, Salanti G. (2019) Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis. Lancet Psychiatry. 2019 Jun 6. pii: S2215-0366(19)30217-2. doi: 10.1016/S2215-0366(19)30217-2.
Other references
NHS Digital. Prescription cost analysis: England 2018. 28 March 2019.
Cipriani A, Furukawa TA, Salanti G, et al. (2018) Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 2018; published online Feb 21. http://dx.doi.org/10.1016/S0140-6736(17)32802-7.
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thanks,useful
Very interesting – particularly the threshold of 150mg for VFX, as if memory serves up to that dose it’s more or less an SSRI and the effect on noradrenaline kicks in from 150mg upwards – which would explain why you get more side effects above this, but it’s interesting that effectiveness also drops off.
A possible explanation for the lower effectiveness at higher doses might be that it’s not so much that they work worse at higher doses, but rather that one only increases the doses to the higher levels when the lower doses aren’t working – so the high dose group is made up of the people whose symptoms aren’t responding so well to antidepressants. So I’m not convinced that this paper argues against using high doses – for those patients *specifically*, they may (emphasise *may*) get more benefit from a higher dose than a lower one, whilst still getting less benefit than someone who gets good effects from medication at lower doses. I’d ideally want to follow this up by looking at research specifically looking at this group – where someone isn’t getting as much benefit as you’d hope for at a low dose, will they get better effects (although also more side effects) at higher dose, or is it better to switch to another medication or avoid medication altogether?
Also interesting to see the drop off in effectiveness above 30mg for MTZ – received wisdom is that it’s sedative up to that dose but tends to be less so above it, due to increasing relative effects on receptors it has lower affinity for (I can’t remember which). So again it’s interesting that the effectiveness threshold coincides with a threshold at which apparently the way it works changes somewhat.