Re: Antidepressants and the serotonin hypothesis of depression
Dear Editor,
Liz Tucker says we cited only two references to support the statement that antidepressants are an effective treatment, but in fact we cited five [1-5]. As well as the meta-analyses of Cipriani et al [1] and Furukawa et al [2] we cited the NICE Depression Guideline, which is not simply based on the conclusions of published literature, but on NICE’s own network meta-analyses of the trial evidence [3,6]. In addition we quoted a patient-level analysis by Hieronymus et al who reported that SSRIs were still superior to placebo among patients who did not experience side-effects, arguing against the claim that antidepressants outperform placebo only because of the increased expectation of improvement in those who experience side-effects and identify they are on active treatment [4]. We also cited Stone et al’s most recent patient-level analysis which reported that the small average advantage of antidepressants over placebo is due to around 25% of patients on active treatment experiencing a large response compared to only around 10% of those on placebo [5].
Tucker further states that a 1.8 improvement in the Hamilton Rating Scale for Depression (HRSD) would be too small for a clinician to identify, but the 1.8 points is not the average improvement for people taking an antidepressant, it’s the average benefit over and above that for a placebo. Stone et al’s analysis shows that patients taking the active drug actually improve on average by 9.8 points on the HRSD, while those on placebo have an average improvement of 8.0 points [5]. A nearly 10 point improvement on the HRSD is well above the minimum clinically important difference.
In practice, many patients experience significant benefit from taking an antidepressant, which we can reassure them is not simply a placebo response. If they express a preference for antidepressant treatment over psychological therapy on the basis of their prior experience practitioners should respect that and prescribe them. However, discussion of the potential side-effects and potential difficulties stopping treatment later should be discussed first so that patients can make an informed decision, and patients’ responses to taking antidepressants should be carefully monitored as we indicated in our editorial.
1. Cipriani A, Furukawa TA, Salanti G, et al. 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;391:1357-66. doi:10.1016/S0140-6736(17)32802-7 pmid:29477251
2. Furukawa TA, Maruo K, Noma H, et al. Initial severity of major depression and efficacy of new generation antidepressants: individual participant data meta-analysis. Acta Psychiatr Scand 2018;137:450-8. doi:10.1111/acps.12886 pmid:29611870
3. NICE. Depression in adults: treatment and management. 2022. www.nice.org.uk/guidance/ng222
4. 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 2018;23:1731-6. doi:10.1038/mp.2017.147 pmid:29155804
5. Stone MB, Yaseen ZS, Miller BJ, Richardville K, Kalaria SN, Kirsch I. Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis. BMJ 2022;378:e067606. doi:10.1136/bmj-2021-067606. pmid:35918097
6. Kendrick T, Pilling S, Mavranezouli I, Megnin-Viggars O, Ruane C, Eadon H et al. Management of depression in adults: summary of updated NICE guidance BMJ 2022; 378 :o1557 doi:10.1136/bmj.o1557
Competing interests:
TK declares that his employer, the University of Southampton, has received funding from the National Institute for Health Research for his research on the assessment and treatment of depression in primary care, and on testing internet and telephone support to people wanting to come off long term antidepressants. TK was a member of the NICE Depression Guideline Committee. SC has a history of depression and long term antidepressant use.
Rapid Response:
Re: Antidepressants and the serotonin hypothesis of depression
Dear Editor,
Liz Tucker says we cited only two references to support the statement that antidepressants are an effective treatment, but in fact we cited five [1-5]. As well as the meta-analyses of Cipriani et al [1] and Furukawa et al [2] we cited the NICE Depression Guideline, which is not simply based on the conclusions of published literature, but on NICE’s own network meta-analyses of the trial evidence [3,6]. In addition we quoted a patient-level analysis by Hieronymus et al who reported that SSRIs were still superior to placebo among patients who did not experience side-effects, arguing against the claim that antidepressants outperform placebo only because of the increased expectation of improvement in those who experience side-effects and identify they are on active treatment [4]. We also cited Stone et al’s most recent patient-level analysis which reported that the small average advantage of antidepressants over placebo is due to around 25% of patients on active treatment experiencing a large response compared to only around 10% of those on placebo [5].
Tucker further states that a 1.8 improvement in the Hamilton Rating Scale for Depression (HRSD) would be too small for a clinician to identify, but the 1.8 points is not the average improvement for people taking an antidepressant, it’s the average benefit over and above that for a placebo. Stone et al’s analysis shows that patients taking the active drug actually improve on average by 9.8 points on the HRSD, while those on placebo have an average improvement of 8.0 points [5]. A nearly 10 point improvement on the HRSD is well above the minimum clinically important difference.
In practice, many patients experience significant benefit from taking an antidepressant, which we can reassure them is not simply a placebo response. If they express a preference for antidepressant treatment over psychological therapy on the basis of their prior experience practitioners should respect that and prescribe them. However, discussion of the potential side-effects and potential difficulties stopping treatment later should be discussed first so that patients can make an informed decision, and patients’ responses to taking antidepressants should be carefully monitored as we indicated in our editorial.
1. Cipriani A, Furukawa TA, Salanti G, et al. 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;391:1357-66. doi:10.1016/S0140-6736(17)32802-7 pmid:29477251
2. Furukawa TA, Maruo K, Noma H, et al. Initial severity of major depression and efficacy of new generation antidepressants: individual participant data meta-analysis. Acta Psychiatr Scand 2018;137:450-8. doi:10.1111/acps.12886 pmid:29611870
3. NICE. Depression in adults: treatment and management. 2022. www.nice.org.uk/guidance/ng222
4. 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 2018;23:1731-6. doi:10.1038/mp.2017.147 pmid:29155804
5. Stone MB, Yaseen ZS, Miller BJ, Richardville K, Kalaria SN, Kirsch I. Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis. BMJ 2022;378:e067606. doi:10.1136/bmj-2021-067606. pmid:35918097
6. Kendrick T, Pilling S, Mavranezouli I, Megnin-Viggars O, Ruane C, Eadon H et al. Management of depression in adults: summary of updated NICE guidance BMJ 2022; 378 :o1557 doi:10.1136/bmj.o1557
Competing interests: TK declares that his employer, the University of Southampton, has received funding from the National Institute for Health Research for his research on the assessment and treatment of depression in primary care, and on testing internet and telephone support to people wanting to come off long term antidepressants. TK was a member of the NICE Depression Guideline Committee. SC has a history of depression and long term antidepressant use.