I find it concerning that the authors pay no attention to the use of Shared Decision Making regarding the use of anti-depressants. Many patients have and continue to benefit from being prescribed an anti-depressant. It is important within prescribing that patients' views, experience and preferences are given due regard.
We appreciate the interest in our article by Jauhar and colleagues and welcome the opportunity to address a number of misleading points in their letter.
No argument they raise undermines our central points: antidepressants do not demonstrate a clinically important difference from placebo according to any suggested threshold, including that proposed by NICE, empirical correlation with clinician evaluation or other means. There is no conclusive evidence of an above-average response sub-group so far demonstrated. The evidence for relapse prevention properties is highly problematic because of confounding by withdrawal effects. Common adverse effects are well-established, a...
We appreciate the interest in our article by Jauhar and colleagues and welcome the opportunity to address a number of misleading points in their letter.
No argument they raise undermines our central points: antidepressants do not demonstrate a clinically important difference from placebo according to any suggested threshold, including that proposed by NICE, empirical correlation with clinician evaluation or other means. There is no conclusive evidence of an above-average response sub-group so far demonstrated. The evidence for relapse prevention properties is highly problematic because of confounding by withdrawal effects. Common adverse effects are well-established, and there are some worrying signals about rare but serious adverse effects, on which we need more data. Quibbling over whether antidepressants cause withdrawal in 30%, 40% or 50% of people misses the more important public health point that any of these proportions means that millions of people are at risk of either suffering in coming off their drugs or being forced to stay on them because of the aversive effects of coming off them. While more studies of this neglected area are always welcome to help define the problem more precisely, authorities have already sensibly acknowledged that the problem is vast enough to require decisive action.[1–3]
Efficacy
The principal argument put forward by Jauhar and colleagues is that we were wrong to suggest that the difference between antidepressants and placebo is clinically insignificant. This ignores the key point that the modest difference between antidepressants and placebo is likely inflated by significant biases including lack of blinding, the use of the placebo run-in design and short trial duration.[4] There is general agreement amongst meta-analyses that the mean difference between placebo and antidepressants is 2 points on the 52-point HDRS scale.[4,5] Any observer would likely judge this a small difference, especially in light of the fact that placebo recipients routinely improve by 7-13 points on the HDRS scale in meta-analyses.[6,7] Indeed, Professor Cipriani, one of the co-authors, has said: “No research evidence or consensus is available about what constitutes a clinically meaningful difference in Hamilton (HDRS) scores, but...a difference of less than 3 points seems unlikely to be regarded as such.”[8] NICE used a cut-off of 0.5 SMD (equivalent to 3.3 HDRS points)4 in its latest draft guidance on depression. [9]
Jauhar and colleagues claim that an analysis [10] of more than 7000 patients from 43 drug trials which aimed to correlate change on the HDRS scale into clinical global impression of change (rating of patients by clinicians from ‘very much worse’ to ‘very much improved’) which is ‘intuitively understood by clinicians’ is not informative both because the study examined people taking mirtazapine, which has differences in receptor targets to SSRIs and SNRIs, and because within-person changes cannot be extrapolated to between-group differences, citing a letter on urinary incontinence. While we accept the possibility that medications with different receptor targets may produce different effects (e.g. being more or less sedating) we do not accept the argument that this study has no relevance to interpreting other drugs because a measurement instrument like a ruler (or the HDRS) is useful whether it is used to measure the length of a single plank or the difference in length between two planks, and can be used whether the plank is made of wood or metal. Having different receptor targets to other drugs has limited relevance and the issue of whether it looks at within-group or between-group differences has no relevance: the point is to correlate change in one metric that has no a priori clinical significance (the 52-point HDRS scale) with one that is understandable to clinicians (degree of clinical improvement). Furthermore, it is not true to say that mirtazapine exerts ‘large effects on HDRS’ compared to other medications: it shows broadly similar effects to other modern antidepressants (2-3 points on the HDRS, according to Appendix in Cipriani et al. (2018).[11]
Indeed, contrary to their assertion that ‘experts’ suggest that a minimally important difference (MID) should only apply to within-groups change and not between-groups change, expert consensus is that MIDs can - and should - inform evaluation of treatment effects (which includes placebo-drug differences),[12–15] and these differences are routinely used for power calculations of studies.[16] As detailed by Revicki et al [17]:
“Although demonstrating responsiveness is a key component to establishing an instrument’s construct validity, it is also important to determine the MID to assist in interpreting statistically significant PRO (patient-reported outcome) results in clinical trials. In addition, the MID for a PRO instrument that is specified as a primary or important secondary endpoint is clearly useful for calculating statistical power and for determining sample sizes for clinical trials.”
On the topic of a suggested alternative, Jauhar and colleagues are notably silent. We therefore think the finding that a change in over 7 points on the HDRS is required for a clinician to measure even a difference of ‘minimally improved’ is a useful guide, also considered useful in a recent paper in World Psychiatry.[18] Other authors, using anchor-based and distribution-based approaches have estimated the MID for the HDRS to be 3 to 8 points, which also included trials with SSRI and SNRI drugs.[19]
The authors then suggest that examining ‘key mood items’ is a more ‘nuanced’ approach which has shown ‘clear benefits’.[20] However, there are several problems with focusing on one item out of the 17 HDRS items (‘depressed mood’) as the paper cited does - firstly, this single item lacks content validity as it fails to capture the many symptoms of depression, as defined, for example, by DSM and ICD, including effects on interest/pleasure, sleep, appetite, suicidality, energy levels, etc.[21,22] Secondly, the item, ‘depressed mood’, reproduced below, itself lacks face validity:
1 |__| These feeling states indicated only on questioning.
2 |__| These feeling states spontaneously reported verbally.
3 |__| Communicates feeling states non-verbally, i.e. through facial expression, posture, voice and tendency to weep.
4 |__| Patient reports virtually only these feeling states in his/her spontaneous verbal and non-verbal communication.
In the analysis performed by Hieronymus and colleagues, the mean of this score at baseline and endpoint were between 1 and 2.[20] It is not self-evident that having to be asked if one feels sad (score = 1) indicates that someone is less depressed than if they report this spontaneously (score = 2). Thirdly, studies looking at this single item are likely subject to reporting bias as the study cohorts consisted entirely of industry-conducted trials that made individual patient data available to them.[20] In any case, the effect size for the depressed mood is still small (SMD=0.40) and below the NICE criterion (0.5 SMD) for a clinically relevant difference.[9] Furthermore, all the same methodological biases that apply to studies employing the full HDRS, also apply to the single item of ‘depressed mood’, likely meaning the true effect is even smaller.[4]
Elsewhere the authors have claimed larger effects for a sub-set of the HDRS-17, the HDRS-6 (Bech-subscale), but in a recent analysis antidepressants only showed an effect size of 0.32 in severe depression (as compared to 0.39 in non-severe depression),[7] hardly different from the finding on the full HDRS-17 scale (0.30), and well below all estimates of MID.19 These subsets of symptoms suffer from the same lack of content validity as a single mood item.[21,22]
Jauhar and colleagues then argue that even if the average effect of antidepressants is small there may be a sub-group with a much larger response. However, analyses that have examined heterogeneity in antidepressant response have so far failed to find evidence for it.[23–26] Unfortunately, Jauhar and colleagues cite a study to support their notion of a strongly responding sub-group [27] that was retracted [28] because the authors used an incorrect analysis. When the proper analysis was conducted the heterogeneity in the antidepressant arms of the trials was not found to be greater than that in the placebo arms of the trials,[25] consistent with all other analyses. Although of course there is variability in the response to both placebo and antidepressant, as the authors state, the cited studies find that the variation is the same for placebo and antidepressant. The simplest explanation for the equal variances is that there are constant treatment effects and there is no treatment heterogeneity.[29]
A final argument made by the authors is that the small size of effect for antidepressants is similar to other medical treatments, citing an analysis by Leucht. [30] This is misleading for two reasons – one, because outcomes for other treatments were mostly based on hard clinical outcomes such as survival or cardiovascular events. If antidepressants were held to the similarly hard clinical outcomes (such as suicide attempts or hospitalisations) rather than subjective symptom rating scales, there would be no effect for antidepressants. Secondly, the duration of treatment in many of the studies in non-psychiatric drugs are months or years (e.g. 5.8 years for aspirin in stroke and heart disease, 10.7 years for metformin in diabetes, 15 years for chemotherapy for breast cancer), highly relevant to the long-term use of these medications, whereas for antidepressants the duration of treatment is generally 6 to 12 weeks.[11] This duration of treatment has limited relevance to the treatment of depression in practice which is often for months, years or even decades.
Lastly, it is also worth considering just how large expectation effects are, which may overshadow any chemical effect of the drug, and account for much or all of the placebo-drug differences in trials. For example, in a negative study of hypericum, sertraline and placebo, people who guessed they were taking one of the active drugs improved by 4.6 to 5.7 points more than those who guessed they were taking placebo, regardless of actual allocation.[31] People allocated to placebo who guessed they were taking sertraline improved by 5.4 points more than people allocated to sertraline who guessed they were taking the placebo.31 This is consistent with another study in which patients were all given escitalopram, but half told what it was (overt) and the other half deceived into thinking it was an active placebo (covert), in which the overt group showed a reduction in MADRS of 9.66 points, 5 points greater than the 4.64 point reduction in the covert group.[32]
In relation to the STAR*D study, although Jauhar and colleagues put forward the unusual position that the original study authors should have the exclusive right to perform the definitive analysis of data, this is not the guiding principle of open science. For example, a re-analysis of paroxetine trials in adolescents found that the data was negative for all eight pre-specified primary and secondary outcomes, although the study was reported as positive by the original authors.[33] The re-analysis of the STAR*D data is important because the original authors decided to switch out the intended primary outcome (HDRS) for the Quick Inventory of Depressive Symptomatology (QIDS) and elected not to use intent-to-treat analysis to derive an exaggerated figure for remission.[34] Pigott and colleagues employed intent-to-treat analysis and found that 108 patients out of 4041 had remitted and not dropped out at 12 months after four cycles of antidepressant treatment according to gold standard treatment.34 Methods used to inflate remission rates in the original publication in a wide variety of ways has been previously discussed,[35] and the overall effect on the HDRS was only 6.55 points,[36] less than the effect of placebo in most studies.[7]
Adverse effects
With regards to adverse effects, one limitation of the field is the lack of long-term studies addressing this issue. As recently pointed out, studies are designed to identify positive effects by their manufacturers, often employing multiple symptom measures to do so.[37] These measures are themselves composites of several symptoms, each interrogated for severity (e.g. the HDRS).[37] In contrast, adverse effects are considered in isolation, with no consideration of their severity, such that their overall impact is impossible to judge, and most studies restrict the adverse effects that are queried. For example, manufacturer studies do not often ask patients about potentially important symptoms such as ‘fogginess’, or ‘emotional numbing’ so a survey with a self-selected group is the only evidence we have of these potentially important adverse effects.[38]
The naturalistic study we cited, used by Jauhar to suggest no relationship to time period, was not set up well to analyse such a relationship as the study authors themselves say: “associations between SEs and…duration may have been weakened by routine clinical measures like lowering of dosages, switching and discontinuation of the antidepressant” and point to the issue of tolerance to adverse effects if patients had used similar drugs before the start of the study.[39] Nevertheless, this study demonstrates that antidepressants cause multiple common adverse effects in the short term as well as the long term.
The authors point to an umbrella review of observational studies [40] but this study suffers from all the same limitation as the observational studies Jauhar and colleagues criticised, and was restricted to a few serious but rare adverse events. These are notoriously difficult to establish reliably, and it is appropriate to have lower standards of evidence for serious harms. Nevertheless, there was “convincing” or “highly suggestive evidence” (of moderate to high quality according to A Measurement Tool to Asses Systematic Reviews-2 (AMSTAR-2) for maternal complications, foetal malformations, osteoporotic fractures, upper GI bleeding and suicidal behaviour among young people among other effects which remained statistically significant in the sensitivity analysis of studies that adjusted for multiple confounders and confounding by indication.[40]
Convincing evidence on common adverse effects comes from a meta-analysis of randomised placebo-controlled antidepressant trials,[5] which therefore does not suffer from confounding by indication, but which may still under-report adverse effects.[41] This meta-analysis found 28 adverse effects to be significantly more common in antidepressants than placebo: including abnormal ejaculation (5.4-fold), anorexia (2.8 fold), nausea (2.5 fold), somnolence (2.3 fold), sweating (2.2 fold), asthenia (1.7-fold), insomnia (1.5 fold), libido decreased (3.5-fold), fatigue (1.7-fold), and nervousness (1.4-fold).[5]
Withdrawal effects
Jauhar and colleagues mis-represent the existing studies when they dismiss evidence for withdrawal effects being common, effectively minimising the important task of helping patients to safely stop these medications. Their view is less widely held these days given that severe and long-lasting withdrawal symptoms are recognised by NICE,[42] the Royal College of Psychiatrists [43] and Public Health England.[2] While a systematic review the authors have been highly critical of did include surveys, it is misleading to suggest that this represents the whole review.[44] This review identified 6 double-blind randomised controlled trials that examined withdrawal effects from antidepressants and a weighted average of these studies found that withdrawal effects occurred in 53.8% of patients (albeit slightly less than the 56.4% found when observational studies and surveys were also included).
Instead the authors cite their own paper which included only studies conducted by drug companies which looked at withdrawal effects after an average of 12 weeks of antidepressant treatment.[45] This review is misleading as it is known that longer duration of treatment gives rise to a greater likelihood of withdrawal effects [3] and so estimates based on these short-term studies will underestimate the chance of withdrawal for half of the patients in England who have been on antidepressants for more than 2 years.[46] Even if we accept the figure derived from this review of 31% (after subtraction of the largest nocebo response rate from one of the studies), this means that more than 2 million of the 7 million people in England who are prescribed antidepressants each month are at risk of having trouble stopping their medication due to withdrawal effects.
It is also false to state that there are no staggered double-blind RCTs conducted on this topic – there are at least two such studies.[47,48] In Rosenbaum et al. (1998) patients were allocated to placebo substitution in a staggered design (with two possible periods for substitution) with both raters and patients blind to this procedure.[47] The proportion of patients who experienced more than 4 withdrawal symptoms in this study were 66% for people taking paroxetine, 60% for sertraline, and 14% for fluoxetine (likely because the 5-8 day interruption period was too short for withdrawal symptoms from this long half-life drug to emerge). The other staggered double-blind study found that people on paroxetine experience, on average, 4 new withdrawal symptoms (when subtracting out active treatment) in 4 days of placebo substitution, though the period was likely too short for withdrawal symptoms for sertraline and fluoxetine to reach significance.[48]
Lewis and colleagues have conducted the first ever double-blind randomised controlled study that examines withdrawal effects from antidepressant over periods longer than a few weeks and recorded a significant increase in withdrawal effects that lasted for at least 9 and perhaps 12 months, demonstrating the existence of long-lasting withdrawal effects.[49] Notably, calculation of the standardised mean difference at 3 months for withdrawal symptoms between the maintenance and discontinuation groups from data provided in the original paper yields an SMD of 0.60 (95% CI 0.41 to 0.78), twice the size of the short-term antidepressant effect.
It is possible that withdrawal effects in the maintenance group in this study could reflect the fact that some patients in this group also stopped treatment (15% of patients in the maintenance arm did so in the study, p.34 of Appendix) and/or the fact that there is some overlap of withdrawal symptoms with adverse effects of antidepressants and with depression and anxiety. The presence of some withdrawal symptoms in the maintenance group does not therefore invalidate the important finding that there was a significant increase in withdrawal effects for many months in the discontinuation group, as reported by the study authors in a rapid response.[50]
Jauhar and colleagues correctly find fault with our statement that relapse occurred almost exclusively within 12 weeks of stopping medication. We should have been more precise: the difference in relapse rates between maintenance and discontinuation arms evident at the end of the study (interpreted as relapse prevention properties) were already present at week 20 (which is 12 weeks after week 8, the point at which medication was stopped for most patients). The difference in relapse rate at the end of the study was 17% (56% -39%). At week 20 the difference in relapse rates between the two groups was already 22% (slightly higher than the final difference between the groups). This is consistent with a withdrawal effect because a true prophylactic drug effect should be evenly distributed over time, but in this study the difference between the two groups was evident within 12 weeks of stopping the drugs (just 27% (12/44) of the length of the follow up period of the study after drugs were stopped). As there should be no temporal correlation between the time of relapse for patients with relapsing-remitting conditions with their own individual periodicity, the clustering of relapse in the weeks following cessation is most plausibly explained by withdrawal effects being mis-diagnosed as relapse.[51,52]
Consistent with the less than impressive evidence of efficacy of antidepressants the recent NICE guidance, now in draft form, albeit with some evidence of bias towards present practice, and a methodology that underestimates the harms of treatments, has moved away from medication as the focus for treatment and now offer 9 treatments ‘equally effective’ for less severe depression and 8 treatments that are ‘equally effective’ for more severe depression than either antidepressants alone or antidepressant in combination with CBT.[9] It is notable that many of these treatments including various forms of psychotherapy, exercise, problem solving therapy, and mindfulness have a more favourable side effect profile than medication.
It is unfortunate that Jauhar and colleagues quibble about marginal differences between mood items and the full HDRS, both consistent with small effects of questionable clinical significance and minimise withdrawal effects, when an important project should be reducing the unnecessary use of these drugs and helping patients to safely stop these medications, which in many cases may cause more harm than benefit.
Acknowledgements: We would like to thank Dr Klaus Munkholm (Cochrane Denmark and Centre for Evidence-Based Medicine Odense) for his useful input into this letter.
References
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We read with interest the opinion piece by Horowitz and Wilcock [1], which highlights ‘considerable uncertainty about the benefit of antidepressant use in the short- and long-term’ and ‘the uncertain balance of benefits and harms’ with antidepressants, within its key learning points. We wish to counter these and address other assertions within their narrative review.
In the section ‘Questions relating to efficacy’, the authors mention meta-analyses with newer generation antidepressants (principally the selective serotonin reuptake inhibitors [SSRIs] and serotonin-noradrenaline reuptake inhibitors [SNRIs]) which show a difference from placebo of around 2 points on the Hamilton Depression Rating Scale (HDRS), noting this does not meet thresholds of 3-, 5- or even 6-point differences, regarded by some as indicating a minimally clinically important difference.
This is taken from data on the antidepressant mirtazapine (neither an SSRI nor SNRI) plotting change in HDRS against clinically important difference [2]. This does not have any relevance for SSRIs or SNRIs, as mirtazapine, by its effects on sleep and somatic symptoms, will exert large effects on HDRS without necessarily affecting low mood. The selection of a point on this graph was not made by authors of the original paper [3], and within-group changes from that selected study cannot be extrapolated to placebo-drug differences: a point made explicit by experts in this area [4], and by us in response to Dr H...
We read with interest the opinion piece by Horowitz and Wilcock [1], which highlights ‘considerable uncertainty about the benefit of antidepressant use in the short- and long-term’ and ‘the uncertain balance of benefits and harms’ with antidepressants, within its key learning points. We wish to counter these and address other assertions within their narrative review.
In the section ‘Questions relating to efficacy’, the authors mention meta-analyses with newer generation antidepressants (principally the selective serotonin reuptake inhibitors [SSRIs] and serotonin-noradrenaline reuptake inhibitors [SNRIs]) which show a difference from placebo of around 2 points on the Hamilton Depression Rating Scale (HDRS), noting this does not meet thresholds of 3-, 5- or even 6-point differences, regarded by some as indicating a minimally clinically important difference.
This is taken from data on the antidepressant mirtazapine (neither an SSRI nor SNRI) plotting change in HDRS against clinically important difference [2]. This does not have any relevance for SSRIs or SNRIs, as mirtazapine, by its effects on sleep and somatic symptoms, will exert large effects on HDRS without necessarily affecting low mood. The selection of a point on this graph was not made by authors of the original paper [3], and within-group changes from that selected study cannot be extrapolated to placebo-drug differences: a point made explicit by experts in this area [4], and by us in response to Dr Horowitz in the past [5].
The HDRS was conceived over 60 years ago, and more nuanced analyses, examining the key mood items, have shown clear benefits for SSRIs, using primary data from randomised double-blind, placebo-controlled trials (RCTs) [6]. The authors cite a review addressing these very issues [7], though do not acknowledge any of these points. That review also addressed practical aspects from trials which suggest the need for more care when evaluating effect sizes, illustrating the points above regarding the HDRS, study level data and practicalities in RCTs that make the expectation of high effect sizes implausible. In critiquing this review, Horowitz and Wilcock argue these inferences are made erroneously on the assumption of “a subgroup with greater than average response.” to SSRIs, and cite a study-level analysis of heterogeneity8 that they claim supports the notion that response to antidepressants is constant across patients – i.e. if the mean antidepressant-placebo difference in a trial is 2 HDRS points, then all patients receiving antidepressants in that study will have a 2-point improvement over placebo. The cited paper correctly acknowledges their analysis cannot disprove a non-constant effect [8]. However, most would agree that a non-constant effect occurs, that data from RCTs are normally distributed, and that there is individual variability in antidepressant and placebo response [9]. Critically, there are patient-level analyses supporting a non-constant effect of antidepressants in depression (Maslej et al., 2021) [10]. Accounting for problems with the HDRS, the ‘number needed to treat’ (NNT) for antidepressants, taken from short-term efficacy trials, is around 7-10, a range which is not dissimilar to many other medical treatments [11].
When the authors consider regulatory issues, they continue, “indeed, longer studies of antidepressants show poor outcomes: in the STAR-D trial only 108 (2.7%), out of 4041 participants who originally enrolled in the study, achieved remission and did not relapse or drop out at the endpoint of the study at 12 months”. However, the original publication in the New England Journal of Medicine [12] shows that STAR-D randomised people with depression to staged treatment with symptom remission as outcome. The reference cited by Horowitz and Wilcock is to a secondary analysis by non-trial authors [13], which is difficult to interpret as 36.7% of patient participants dropped out of the study one month after remission: cumulative remission in the STAR-D study was 67%, though this may be an over-estimate as drop-outs were not included in this figure (and there was no placebo group).
The section on ‘harms of long-term use of antidepressants’ cites a naturalistic study [14] and a self-selected survey [15] in which the survey response rate is not mentioned. Horowitz and Wilcock state that rates of adverse effects are ‘often greater in naturalistic studies of long-term antidepressant users’ (our italics) than those mentioned in 6-12 week efficacy studies’. The authors of the cited naturalistic study state, "We find slightly lower side effects (SE) reporting with prolonged antidepressant use, while no associations are detected between specific SEs and prolonged use. During long-term antidepressant use, all specific SEs seem to persist.“ Horowitz and Wilcock overlooked a recent substantial ‘umbrella review’ of meta-analyses [16], which found a low rate of adverse effects attributable to antidepressants. This is particularly important as this umbrella review included cohorts of people not receiving antidepressants, therefore adjusting for a common problem with observational studies: confounding by indication.
A subsequent paragraph on withdrawal effects with antidepressants notes a recent (2019) Public Health Review acknowledging the very low to moderate quality of the evidence. Horowitz and Wilcock cite a review of the incidence, duration and severity of antidepressant withdrawal reactions [17] to assert that “about half” of patients experience withdrawal symptoms on stopping antidepressants, abruptly or with taper; however, not all evidence is aligned with this contention (e.g. the sample of “half” included self-selected surveys with no mention of response rate; and RCTs indicate substantially lower rates, varying by compound) [18-19]. Randomised placebo-controlled studies with a double-blind staggered design probably represent the best approach to ascertain the relative burden of symptoms which emerge during or after stopping placebo or antidepressant treatment.
Horowitz and Wilcock appear to favour use of the Discontinuation Emergent Signs and Symptoms (DESS) scale15 for assessing antidepressant withdrawal symptoms, although there are potential flaws in the utility of this check-list instrument in research and clinical practice [20]. They cite use of a modified version of the DESS (a 15-item checklist) [21] in a recent RCT of antidepressant treatment discontinuation in UK primary care [22] stating that withdrawal effects were ‘almost triple’ in the discontinuation group. In the original publication, the mean score for withdrawal symptoms was reported as 1.3+2.4 in the maintenance group and 3.1+3.5 in the discontinuation group, with an estimated difference between groups of 1.9 points [95% CI, 1.5-2.3]. Many participants experienced an increase in withdrawal symptoms, regardless of allocation to continued treatment or treatment discontinuation. The further problem of the DESS picking up symptoms of relapse can only be clarified by a fuller examination of the patient level data.
Elucidating the clinical validity of these changes in measures based on rating scales would seem reasonable before any pronouncement about withdrawal effects can be made definitively. Further work, ideally using the double-blind placebo-controlled staggered design, is needed to fully characterise the overall burden of symptoms following the withdrawal of antidepressant treatment (with consideration of incidence, severity, persistence, and impairment). Horowitz and Wilcock make a factual error when reporting findings in this UK study: they say that new depressive episodes (relapses) in the group who had discontinued antidepressants “occurred almost exclusively within 12 weeks of stopping medication, the time during which withdrawal effects were most pronounced”, thus implying these events were not depressive relapses but rather withdrawal symptoms. However, the Kaplan–Meier analysis from the paper clearly indicates that less than half of all relapses occurred within 12 weeks.
It is difficult to draw reliable conclusions from the selective reporting of Horowitz and Wilcock’s viewpoint. The authors appear to have come to their own conclusions, and then selectively cited only the evidence that supports them.
References
[1] Horowitz M, Wilcock M. Newer generation antidepressants and withdrawal effects: reconsidering the role of antidepressants and helping patients to stop. DTB 2022; 60: 7–12.
[2] Leucht S, Fennema H, Engel R, Kaspers-Janssen M, Lepping P, Szegedi A. What does the HAMD mean? J Affect Disord 2013; 148: 243–8.
[3] Moncrieff J, Kirsch I. Empirically derived criteria cast doubt on the clinical significance of antidepressant-placebo differences. Contemp Clin Trials 2015; 43: 60–2.
[4] Furukawa TA. Measuring Clinical Importance in a Trial of Interventions for Mixed Urinary Incontinence. JAMA 2020; 323: 479.
[5] Jauhar S, Marwaha S, Morrison PD, Upthegrove R. Weighing up scientific evidence requires balance, not opinion. The British Journal of Psychiatry 2021; 219: 619–619.
[6] Hieronymus F, Lisinski A, Nilsson S, Eriksson E. Efficacy of selective serotonin reuptake inhibitors in the absence of side effects: a mega-analysis of citalopram and paroxetine in adult depression. Mol Psychiatry 2017; published online July 25. DOI:10.1038/mp.2017.147.
[7] Hieronymus F, Jauhar S, Østergaard SD, Young AH. One (effect) size does not fit at all: Interpreting clinical significance and effect sizes in depression treatment trials. J Psychopharmacol 2020; : 0269881120922950.
[8] Volkmann C, Volkmann A, Müller CA. On the treatment effect heterogeneity of antidepressants in major depression: A Bayesian meta-analysis and simulation study. PLOS ONE 2020; 15: e0241497.
[9] Maslej MM, Furukawa TA, Cipriani A, Andrews PW, Mulsant BH. Individual Differences in Response to Antidepressants: A Meta-analysis of Placebo-Controlled Randomized Clinical Trials. JAMA Psychiatry 2020; 77: 607–17.
[10] Hieronymus F, Lisinski A, Hieronymus M, Näslund J, Eriksson E, Østergaard SD. Determining maximal achievable effect sizes of antidepressant therapies in placebo-controlled trials. Acta Psychiatrica Scandinavica 2021; 144: 300–9.
[11] Leucht S, Hierl S, Kissling W, Dold M, Davis JM. Putting the efficacy of psychiatric and general medicine medication into perspective: review of meta-analyses. The British Journal of Psychiatry 2012; 200: 97–106.
[12] Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, Sertraline, or Venlafaxine-XR after Failure of SSRIs for Depression. New England Journal of Medicine 2006; 354: 1231–42.
[13] Pigott HE, Leventhal AM, Alter GS, Boren JJ. Efficacy and effectiveness of antidepressants: current status of research. Psychother Psychosom 2010; 79: 267–79.
[14] Bet PM, Hugtenburg JG, Penninx BWJH, Hoogendijk WJG. Side effects of antidepressants during long-term use in a naturalistic setting. Eur Neuropsychopharmacol 2013; 23: 1443–51.
[15] Read J, Williams J. Adverse Effects of Antidepressants Reported by a Large International Cohort: Emotional Blunting, Suicidality, and Withdrawal Effects. Curr Drug Saf 2018; 13: 176–86.
[16] Dragioti E, Solmi M, Favaro A, et al. Association of Antidepressant Use With Adverse Health Outcomes: A Systematic Umbrella Review. JAMA Psychiatry 2019; 76: 1241–55.
[17] Davies J, Read J. A systematic review into the incidence, severity and duration of antidepressant withdrawal effects: Are guidelines evidence-based? Addict Behav 2018; published online Sept 4. DOI:10.1016/j.addbeh.2018.08.027.
[18] Jauhar S, Hayes J. The war on antidepressants: What we can, and can’t conclude, from the systematic review of antidepressant withdrawal effects by Davies and Read. Addict Behav 2019; published online Jan 23. DOI:10.1016/j.addbeh.2019.01.025.
[19] Jauhar S, Hayes J, Goodwin GM, Baldwin DS, Cowen PJ, Nutt DJ. Antidepressants, withdrawal, and addiction; where are we now? J Psychopharmacol (Oxford) 2019; : 269881119845799.
[20] Baldwin DS. A personal account of reducing and stopping antidepressant treatment. Int Clin Psychopharmacol 2020; 35: 194–200.
[22] Lewis G, Marston L, Duffy L, et al. Maintenance or Discontinuation of Antidepressants in Primary Care. New England Journal of Medicine 2021; 385: 1257–67.
Thank you for highlighting this paper which attempts to answer an important clinical question.
I read the DTB summary which reflects the published abstract and the authors' conclusions. Unfortunately this paper has a major flaw as the main CYP "interaction" seen in the study group and therefore studied was Atorvatsatin / Rivaroxaban .
It has been well established that there is no clinically significant interaction between atorvastatin and rivaroxaban whatever the "clinical practice research database" might say.
Therefore this study finds mainly that there is no interaction between two pairs of drugs that do not interact- atorvastatin and rivaroxaban and digoxin and rivaroxaban.
The authors incorrectly extrapolates this finding to actual CYP 3a4 inhibitors although there is an exploratory finding of enhanced bleeding risk with these agents.
In our busy world people may not have time to delve beyond the abstract and key points and may make an erroneous prescribing decision based on this.
The finding related to SSRI use is very valuable and should be born in mind.
We commend the author’s endeavours to present an unbiased review concerning depot triamcinolone. However, this review cannot be judged a total success; there are numerous flaws that cry out to be corrected. The most important issue is the excessive focus on potential side effects, that are generally regarded as of minor significance.
We understand that this is a somewhat lengthy comment, but since the journal states that ‘critique and disagreement are important features of science’, we hope that we are allowed to express our opinion in order to be able to promote further debate.
The title, negatively framed, states ‘Still no place for depot triamcinolone in hay fever?’ and we get the feeling that the author already skipped the question mark and directly continued with the key learning point that ‘in 1999, Drug and Therapeutics Bulletin (DTB) noted that despite the likelihood that a single injection of triamcinolone will relieve hay fever symptoms, there was uncertainty about the efficacy and safety of repeated administration’.1
This notion is too easily repeated in the current conclusion. The first part of the first sentence of the conclusion section informs us again that a single injection of triamcinolone has likelihood that it will relieve hay fever symptoms. The fact that it probably causes symptom reduction should be enough reason to explore the possible indications for this therapy.
Therefore, the only logical conclusion should have been that...
We commend the author’s endeavours to present an unbiased review concerning depot triamcinolone. However, this review cannot be judged a total success; there are numerous flaws that cry out to be corrected. The most important issue is the excessive focus on potential side effects, that are generally regarded as of minor significance.
We understand that this is a somewhat lengthy comment, but since the journal states that ‘critique and disagreement are important features of science’, we hope that we are allowed to express our opinion in order to be able to promote further debate.
The title, negatively framed, states ‘Still no place for depot triamcinolone in hay fever?’ and we get the feeling that the author already skipped the question mark and directly continued with the key learning point that ‘in 1999, Drug and Therapeutics Bulletin (DTB) noted that despite the likelihood that a single injection of triamcinolone will relieve hay fever symptoms, there was uncertainty about the efficacy and safety of repeated administration’.1
This notion is too easily repeated in the current conclusion. The first part of the first sentence of the conclusion section informs us again that a single injection of triamcinolone has likelihood that it will relieve hay fever symptoms. The fact that it probably causes symptom reduction should be enough reason to explore the possible indications for this therapy.
Therefore, the only logical conclusion should have been that in specific cases this therapy might be used, but that possible side effects - though rarely seen in a clinical relevant degree - should be taken into account. Specific cases being, some of those 10% patients who do not obtain enough relief with the current gold standard intranasal steroids and antihistamines. Each year we see patients who cannot get out of their houses because of the severity of their symptoms despite ‘modern, safe and effective treatments’. In our practice a single injection is all we need for patients suffering from severe hay fever.
The second part however, states ‘there remains uncertainty about the efficacy and safety of repeated administration’. But, this is the answer to a completely different question – namely “place for repeated depot triamcinolone?” – that should not be used in the same sentence.
Likewise DTB states that if ‘the patient experiences prolonged symptoms as a result of multiple allergies, several injections may be necessary, which increases the risk of severe adverse effects’. But, though that might be true, it again is not the answer to the question whether a place exists for triamcinolone in hay fever. The review question was not “does a place exist for multiple triamcinolone injections in patients with multiple allergies?”.
And if the season is exceptionally severe, the other reason mentioned for prescribing several injections, we think that this circumstance would probably also lead to a higher prescription of oral steroids with the same profile of side effects.
The DTB recommended a brief course of oral prednisolone in patients with severe hay fever as this allows flexibility in dosing and the option to stop treatment if unwanted effects occur. Recently, an article was published comparing the pharmacokinetics of intramuscular and oral betamethasone and dexamethasone. Based on these data we see that the pharmacokinetics and pharmacodynamics (effects on glucose and plasma cortisol) are similar for both the oral and intramuscular preparations for dexamethasone and betamethasone.2 Why expect more side effects for intramuscular corticosteroids as they show similar pharmacokinetic- and dynamic characteristics with oral preparations?
Why not just follow the clinically most important question: how effective is a single intramuscular injection for hay fever? As recently described, in our military population we clearly see an indication in case of severe symptoms. Our patients are extremely satisfied with this therapy; therefore we concur with the notion that ‘continued interest by patients in using this treatment’ exists.
The current review shows that in 1999 the DTB already described a double-blind placebo-controlled trial, which included 38 patients with severe symptoms of hay fever and reported an improvement or resolution of symptoms in 94% of patients given triamcinolone compared with 10% given a placebo.3 That was and is quite an effect and it is incomprehensible that the authors in 1999 and now come to a conclusion that there is no place for this therapy. Especially considering that DTB further quotes that in all the double-blind placebo-controlled trials, a statistically significant effect on symptom relief was shown.
The DTB authors then and now, however, are obsessed with finding unwanted effects. Even though the 1999 review concluded that such side effects were not seen often, the DTB concluded that there was a marked lack of controlled trial data on the likelihood of such effects. However, side effects are preferably assessed in the total population instead of in trials. According to the DTB review 222,000 prescriptions for triamcinolone acetonide injection were dispended in primary care in England in 2018, and we suppose that this will have been about the same amount every year for the last few decades. Whether prescribed for hay fever or for other indications, major clinical side effects of this therapy would have surfaced by now with these amounts of injections, but they did not. Many articles in various disciplines such as dermatology and pulmonology conclude that the profile of side effects is not that disastrous.4,5
Side effects are inherent to every therapy. The chance of occurrence and their severity is something that should be discussed with patients and should lead to well-informed patients and doctors performing shared decision-making. Side effects should be weighed against disease burden/decreased quality of life. Even severe side effects are not a reason to completely withhold or abandon the therapy if the medication is highly effective.
Østergaard et al.6 noted that the data did not highlight any concerns regarding long-lasting suppression of plasma cortisol, the possibility of a longstanding influence on stress reaction, or the risk of serious tissue atrophy following a single intramuscular injection of corticosteroid for hay fever. And to quote Storrs: ‘there is good reason to believe that the marked and long-lasting hypothalamic-pituitary-adrenal axis suppression associated with even one 40-mg injection is of theoretical rather than practical importance’.
According to Sackett et al.7 the practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research. Why does DTB fail to see that the manuscript by Ostergaard et al.6 is the best available external evidence?
The DTB review, in our opinion, creates ‘disinformation’ by putting the pro argument – based on a systematic review - by Østergaard et al. somewhat at the same level of evidence as two subsequent negative comments by Barnes & Kuitert8, and Bousquet9. The stake holding counter arguments by Østergaard to the comments by Bousquet, and Barnes & Kuitert are unfortunately completely ignored; it would have been only fair to mention these as well.
As for the negative arguments the DTB further mentions Nasser10, and Scadding et al.11 We wonder if the DTB noticed that Bousquet, Nasser and Scadding is actually three occurrences of the same argument. The only reference to the fact that ‘adverse effects outweigh the demonstrated clinical benefit’ in the International Consensus Statement by Scadding et al. is the extremely rare case of avascular necrosis by Nasser. Also please note that this avascular necrosis case, also referenced by Bousquet, occurred in a patient with more than just a single 40 mg triamcinolone injection per year.
Another point that is ignored is the fact that a single intramuscular injection is extremely cost-effective. The interested reader should look for the price of a single depot triamcinolone and compare this with nasal sprays, antihistamines, oral steroids and especially immunotherapy. Østergaard et al., in the response to Barnes and Kuitert, wrote that they think that the reason for the lack of studies remains unclear. We dare to suggest that the reason is quite simply financially. The alarming number of conflicts of interest disclosed by most authors of guidelines on this topic, in combination with the fact that the majority of clinical studies in allergy are supported by the pharmaceutical industry, should be a reason for grave concern.
DTB also mentions the retrospective study based on Danish registry databases as a safety issue. DTB fails to note that according to Aasbjerg et al.12: 1) ‘rhinitis treatment with depot-steroid injections was defined as individuals receiving at least one depot-steroid injection ..’, so the study does not show if the patients developing diabetes and osteoporosis had one or more injection, and it does not show if one injection concerns 40 mg triamcinolone or 80 mg methylprednisolone; 2) ‘we do not know if the cumulative effect of several steroid injections plays a role’; 3) ‘among the cases diagnosed with diabetes based on the prescription of glucose lowering drugs, the number who remained on glucose lowering treatment decreased in both groups during the observation period, ending up at only 40% and 51% for steroids and SCIT respectively’ (e.g. more in the SCIT group!); 4) ‘a possible confounder in our study is that doctors might initiate – more? - screening for osteoporosis and/or diabetes following treatment with steroids compared to immunotherapy which is not associated with the same risk factors. Accordingly, more individuals might be diagnosed when treated with steroids as a result of the screening’.
And the most relevant remark is that Aasbjerg compared depot-steroid to immunotherapy; that is comparing apples to oranges. Would the outcome be totally different if depot steroids were compared with oral steroids? We think not.
Moreover, the DTB review stating that ‘immunotherapy may be an option for patients requiring frequent oral corticosteroid rescue’ makes it look like these therapies are mutually exclusive. But they are not. We offer immunotherapy to the same patient group with severe hay fever symptoms. This, because they visit us in the season at a moment they experience a lot of complaints, however we are unable to start immunotherapy since it is advised not to start during the pollen season. Furthermore, immunotherapy takes some years for optimal effect, so patients sometimes still have a couple of years of incapacitating complaints before the desensitisation works. Also, not all our military patients can adhere to the strict schemes of immunotherapy due to their professional duties.
Last but not least, to get back to the topic of side effects, have the authors of the DTB reviews ever experienced a patient getting an anaphylactic shock due to immunotherapy? That is a truly scary situation! Unlike the avascular hip necrosis described by Nasser, it is one we meet on a yearly base.
Before concurring that a short course of oral corticosteroids is recommended over a depot injectable preparation as DTB suggests, the trial that needs to be done is one that shows that oral steroids are superior with less side effects. At this point there is, to the best of our knowledge, no published evidence whatsoever that oral corticosteroids are more effective with less side effects than a single injection triamcinolone in case of severe hay fever.
Therefore, we simply cannot agree with turning around the burden of proof as implied in the sentence that ‘this product should not be used, until clear evidence of its advantages over other hay fever treatments, including oral prednisolone, become available’.
1. Any place for depot triamcinolone in hay fever? Drug and Therapeutics Bulletin. 1999;37(3):17-18.
2. Jobe AH, Milad MA, Peppard T, Jusko WJ. Pharmacokinetics and Pharmacodynamics of Intramuscular and Oral Betamethasone and Dexamethasone in Reproductive Age Women in India. Clinical and translational science. 2020;13(2):391-399.
3. Axelsson A, Lindholm B. The effect of triamcinolone acetonide on allergic and vasomotor rhinitis. Acta oto-laryngologica. 1972;73(1):64-67.
4. Thomas LW, Elsensohn A, Bergheim T, Shiu J, Ganesan A, Secrest A. Intramuscular Steroids in the Treatment of Dermatologic Disease: A Systematic Review. Journal of drugs in dermatology : JDD. 2018;17(3):323-329.
5. Kirkland SW, Cross E, Campbell S, Villa-Roel C, Rowe BH. Intramuscular versus oral corticosteroids to reduce relapses following discharge from the emergency department for acute asthma. The Cochrane database of systematic reviews. 2018;6:Cd012629.
6. Ostergaard MS, Ostrem A, Soderstrom M. Hay fever and a single intramuscular injection of corticosteroid: a systematic review. Primary care respiratory journal : journal of the General Practice Airways Group. 2005;14(3):124-130.
7. Sackett DL, Rosenberg WMC, Gray JAM, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn't. BMJ (Clinical research ed). 1996;312(7023):71-72.
8. Barnes N, Kuitert L. Treatment of hay fever with a single intramuscular (i.m.) injection of corticosteroid. Primary care respiratory journal : journal of the General Practice Airways Group. 2005;14(6):320; author reply 321-322.
9. Bousquet J. Primum non nocere. Primary care respiratory journal : journal of the General Practice Airways Group. 2005;14(3):122-123.
10. Nasser SM, Ewan PW. Lesson of the week: Depot corticosteroid treatment for hay fever causing avascular necrosis of both hips. BMJ (Clinical research ed). 2001;322(7302):1589-1591.
11. Scadding GK, Kariyawasam HH, Scadding G, et al. BSACI guideline for the diagnosis and management of allergic and non-allergic rhinitis (Revised Edition 2017; First edition 2007). Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2017;47(7):856-889.
12. Aasbjerg K, Torp-Pedersen C, Vaag A, Backer V. Treating allergic rhinitis with depot-steroid injections increase risk of osteoporosis and diabetes. Respiratory medicine. 2013;107(12):1852-1858.
I find it concerning that the authors pay no attention to the use of Shared Decision Making regarding the use of anti-depressants. Many patients have and continue to benefit from being prescribed an anti-depressant. It is important within prescribing that patients' views, experience and preferences are given due regard.
We appreciate the interest in our article by Jauhar and colleagues and welcome the opportunity to address a number of misleading points in their letter.
No argument they raise undermines our central points: antidepressants do not demonstrate a clinically important difference from placebo according to any suggested threshold, including that proposed by NICE, empirical correlation with clinician evaluation or other means. There is no conclusive evidence of an above-average response sub-group so far demonstrated. The evidence for relapse prevention properties is highly problematic because of confounding by withdrawal effects. Common adverse effects are well-established, a...
Show MoreWe read with interest the opinion piece by Horowitz and Wilcock [1], which highlights ‘considerable uncertainty about the benefit of antidepressant use in the short- and long-term’ and ‘the uncertain balance of benefits and harms’ with antidepressants, within its key learning points. We wish to counter these and address other assertions within their narrative review.
In the section ‘Questions relating to efficacy’, the authors mention meta-analyses with newer generation antidepressants (principally the selective serotonin reuptake inhibitors [SSRIs] and serotonin-noradrenaline reuptake inhibitors [SNRIs]) which show a difference from placebo of around 2 points on the Hamilton Depression Rating Scale (HDRS), noting this does not meet thresholds of 3-, 5- or even 6-point differences, regarded by some as indicating a minimally clinically important difference.
This is taken from data on the antidepressant mirtazapine (neither an SSRI nor SNRI) plotting change in HDRS against clinically important difference [2]. This does not have any relevance for SSRIs or SNRIs, as mirtazapine, by its effects on sleep and somatic symptoms, will exert large effects on HDRS without necessarily affecting low mood. The selection of a point on this graph was not made by authors of the original paper [3], and within-group changes from that selected study cannot be extrapolated to placebo-drug differences: a point made explicit by experts in this area [4], and by us in response to Dr H...
Show MoreDear D&T team,
Thank you for highlighting this paper which attempts to answer an important clinical question.
I read the DTB summary which reflects the published abstract and the authors' conclusions. Unfortunately this paper has a major flaw as the main CYP "interaction" seen in the study group and therefore studied was Atorvatsatin / Rivaroxaban .
It has been well established that there is no clinically significant interaction between atorvastatin and rivaroxaban whatever the "clinical practice research database" might say.
Therefore this study finds mainly that there is no interaction between two pairs of drugs that do not interact- atorvastatin and rivaroxaban and digoxin and rivaroxaban.
The authors incorrectly extrapolates this finding to actual CYP 3a4 inhibitors although there is an exploratory finding of enhanced bleeding risk with these agents.
In our busy world people may not have time to delve beyond the abstract and key points and may make an erroneous prescribing decision based on this.
The finding related to SSRI use is very valuable and should be born in mind.
We commend the author’s endeavours to present an unbiased review concerning depot triamcinolone. However, this review cannot be judged a total success; there are numerous flaws that cry out to be corrected. The most important issue is the excessive focus on potential side effects, that are generally regarded as of minor significance.
We understand that this is a somewhat lengthy comment, but since the journal states that ‘critique and disagreement are important features of science’, we hope that we are allowed to express our opinion in order to be able to promote further debate.
The title, negatively framed, states ‘Still no place for depot triamcinolone in hay fever?’ and we get the feeling that the author already skipped the question mark and directly continued with the key learning point that ‘in 1999, Drug and Therapeutics Bulletin (DTB) noted that despite the likelihood that a single injection of triamcinolone will relieve hay fever symptoms, there was uncertainty about the efficacy and safety of repeated administration’.1
Show MoreThis notion is too easily repeated in the current conclusion. The first part of the first sentence of the conclusion section informs us again that a single injection of triamcinolone has likelihood that it will relieve hay fever symptoms. The fact that it probably causes symptom reduction should be enough reason to explore the possible indications for this therapy.
Therefore, the only logical conclusion should have been that...