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NIHR Signal The most effective antidepressants for adults revealed in major review

Published on 3 April 2018

doi: 10.3310/signal-00580

Antidepressants are effective to treat moderate to severe depression in adults. Five antidepressants appear more effective and better tolerated than others.

A major review of 522 antidepressant trials found that all of the 21 drugs studied performed better than placebo, in short-term trials measuring response to treatment. However, effectiveness varied widely.

Researchers ranked drugs by effectiveness and acceptability after eight weeks of treatment. Several drugs were more effective and were stopped by fewer people than others:

  • escitalopram
  • paroxetine
  • sertraline
  • agomelatine
  • mirtazapine.

The review provides new evidence which may help people decide which antidepressant to choose first-line for moderate to severe depression. However, it did not assess antidepressants compared to other treatments such as cognitive behavioural therapy, or treatments in combination. Though there are some concerns over items not reported by individual trials, this review is likely to be reliable. It is extensive, included only placebo controlled double blind trials and searched successfully for unpublished trials.

Share your views on the research.

Why was this study needed?

Depression is a common condition, affecting an estimated 1 in 10 adults at some point in their lives. Antidepressants are widely prescribed in primary and secondary care, along with psychological interventions such as cognitive behavioural or interpersonal therapy. There is conflicting evidence to guide which antidepressants should be prescribed first-line, although NICE recommends a selective serotonin reuptake inhibitor (SSRI).

There has been uncertainty in recent years about the effectiveness of antidepressants. Their mode of action is poorly understood, and improvement in mood tends to be modest. One 2008 meta-analysis suggested that antidepressants gave little benefit over placebo for mild to moderate depression.

This new analysis went to some lengths to find unpublished studies and additional data from published studies, to give us the best overview of the current state of research.

What did this study do?

This systematic review and network meta-analysis compared 21 antidepressants with placebo or each other, directly within trials and indirectly across trials. They included 522 double-blind randomised controlled trials of 116,477 adults with moderate to severe depression.

More than 100 trials were previously unpublished. As well as publication databases, international trial registers and drug approval websites, the researchers had contacted all pharmaceutical companies marketing antidepressants to ask for unpublished studies.

The antidepressants were compared for effectiveness (at least 50% improvement in symptoms) and acceptability (assessed as drop-out rate). They found 380 trials at possible risk of bias due mainly to lack of reporting of randomisation methods, and 46 at high risk.  However, the trials were all placebo controlled.

What did it find?

  • All 21 antidepressants were more likely to produce a treatment response after eight weeks treatment than a placebo. The most effective antidepressant compared to placebo was the tricyclic antidepressant amitriptyline, which increased the chances of treatment response more than two-fold (odds ratio [OR] 2.13, 95% credible interval [CrI] 1.89 to 2.41). The least effective was the serotonin and noradrenaline reuptake inhibitor reboxetine, which increased treatment response by 37% (OR 1.37, 95% CrI 1.16 to 1.63).
  • Drop-out rates by eight weeks of treatment were similar to placebo for the majority of antidepressants. People were 30% more likely to stop taking the tricyclic clomipramine than placebo (OR 1.30, 95% CrI 1.01 to 1.68) and slightly less likely to stop taking agomelatine (an “atypical” antidepressant) or the SSRI fluoxetine (OR for agomelatine 0.84, 95% CrI 0.72 to 0.97; OR for fluoxetine 0.88, 95% CrI 0.8 to 0.96).
  • In head-to-head comparisons between the drugs, five were identified as having a combination of better effectiveness and lower drop-out rates, compared to others: the SSRIs escitalopram, paroxetine and sertraline, and atypicals agomelatine and mirtazapine. Reboxetine (atypical), trazodone (similar to a tricyclic) and fluvoxamine (SSRI) were identified as having lower effectiveness and higher drop-out rates.
  • Though absolute effect sizes were not reported in the results, the researchers described the effect sizes as “modest”. However, they also said that “non-response to treatment will occur.”

What does current guidance say on this issue?

The NICE 2009 guideline on depression advises that people with moderate to severe depression should be offered an antidepressant and psychological therapy such as cognitive behavioural therapy or interpersonal therapy. It says the antidepressant prescribed “should normally be an SSRI in a generic form because SSRIs are equally effective as other antidepressants and have a favourable risk-benefit ratio.”

The guideline warns that venlafaxine is more associated with risk of death from overdose than other SSRIs, while “tricyclic antidepressants, except for lofepramine, are associated with the greatest risk in overdose.”

The guideline, last updated in 2016, is under review.

What are the implications?

The findings are of interest to GPs and psychiatrists, who need to decide on the best initial treatment for adults with moderate to severe depression. The comparative data may help doctors select drugs with better efficacy and side-effects.

However, treatment choice will be guided by an individual patient's circumstances and preferences. The meta-analysis was unable to look at the potentially different effects of treatment on subgroups based on age, sex, the severity of symptoms or duration of illness. 

The review did not consider combined drug and psychological treatments, as recommended by NICE for moderate to severe depression, or long-term effects which limit its applicability.

Citation and Funding

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. [Epub ahead of print].

This project was funded by the National Institute for Health Research Oxford Health Biomedical Research Centre (BRC-1215-20005) and the Japan Society for the Promotion of Science.

Bibliography

Parikh SV, Kennedy SH. More data, more answers: picking the optimal antidepressant. Lancet 2018.

NICE. Depression in adults: recognition and management. CG90. London: National Institute for Health and Care Excellence; 2009.

Why was this study needed?

Depression is a common condition, affecting an estimated 1 in 10 adults at some point in their lives. Antidepressants are widely prescribed in primary and secondary care, along with psychological interventions such as cognitive behavioural or interpersonal therapy. There is conflicting evidence to guide which antidepressants should be prescribed first-line, although NICE recommends a selective serotonin reuptake inhibitor (SSRI).

There has been uncertainty in recent years about the effectiveness of antidepressants. Their mode of action is poorly understood, and improvement in mood tends to be modest. One 2008 meta-analysis suggested that antidepressants gave little benefit over placebo for mild to moderate depression.

This new analysis went to some lengths to find unpublished studies and additional data from published studies, to give us the best overview of the current state of research.

What did this study do?

This systematic review and network meta-analysis compared 21 antidepressants with placebo or each other, directly within trials and indirectly across trials. They included 522 double-blind randomised controlled trials of 116,477 adults with moderate to severe depression.

More than 100 trials were previously unpublished. As well as publication databases, international trial registers and drug approval websites, the researchers had contacted all pharmaceutical companies marketing antidepressants to ask for unpublished studies.

The antidepressants were compared for effectiveness (at least 50% improvement in symptoms) and acceptability (assessed as drop-out rate). They found 380 trials at possible risk of bias due mainly to lack of reporting of randomisation methods, and 46 at high risk.  However, the trials were all placebo controlled.

What did it find?

  • All 21 antidepressants were more likely to produce a treatment response after eight weeks treatment than a placebo. The most effective antidepressant compared to placebo was the tricyclic antidepressant amitriptyline, which increased the chances of treatment response more than two-fold (odds ratio [OR] 2.13, 95% credible interval [CrI] 1.89 to 2.41). The least effective was the serotonin and noradrenaline reuptake inhibitor reboxetine, which increased treatment response by 37% (OR 1.37, 95% CrI 1.16 to 1.63).
  • Drop-out rates by eight weeks of treatment were similar to placebo for the majority of antidepressants. People were 30% more likely to stop taking the tricyclic clomipramine than placebo (OR 1.30, 95% CrI 1.01 to 1.68) and slightly less likely to stop taking agomelatine (an “atypical” antidepressant) or the SSRI fluoxetine (OR for agomelatine 0.84, 95% CrI 0.72 to 0.97; OR for fluoxetine 0.88, 95% CrI 0.8 to 0.96).
  • In head-to-head comparisons between the drugs, five were identified as having a combination of better effectiveness and lower drop-out rates, compared to others: the SSRIs escitalopram, paroxetine and sertraline, and atypicals agomelatine and mirtazapine. Reboxetine (atypical), trazodone (similar to a tricyclic) and fluvoxamine (SSRI) were identified as having lower effectiveness and higher drop-out rates.
  • Though absolute effect sizes were not reported in the results, the researchers described the effect sizes as “modest”. However, they also said that “non-response to treatment will occur.”

What does current guidance say on this issue?

The NICE 2009 guideline on depression advises that people with moderate to severe depression should be offered an antidepressant and psychological therapy such as cognitive behavioural therapy or interpersonal therapy. It says the antidepressant prescribed “should normally be an SSRI in a generic form because SSRIs are equally effective as other antidepressants and have a favourable risk-benefit ratio.”

The guideline warns that venlafaxine is more associated with risk of death from overdose than other SSRIs, while “tricyclic antidepressants, except for lofepramine, are associated with the greatest risk in overdose.”

The guideline, last updated in 2016, is under review.

What are the implications?

The findings are of interest to GPs and psychiatrists, who need to decide on the best initial treatment for adults with moderate to severe depression. The comparative data may help doctors select drugs with better efficacy and side-effects.

However, treatment choice will be guided by an individual patient's circumstances and preferences. The meta-analysis was unable to look at the potentially different effects of treatment on subgroups based on age, sex, the severity of symptoms or duration of illness. 

The review did not consider combined drug and psychological treatments, as recommended by NICE for moderate to severe depression, or long-term effects which limit its applicability.

Citation and Funding

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. [Epub ahead of print].

This project was funded by the National Institute for Health Research Oxford Health Biomedical Research Centre (BRC-1215-20005) and the Japan Society for the Promotion of Science.

Bibliography

Parikh SV, Kennedy SH. More data, more answers: picking the optimal antidepressant. Lancet 2018.

NICE. Depression in adults: recognition and management. CG90. London: National Institute for Health and Care Excellence; 2009.

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

Published on 21 February 2018

A Cipriani, T Furukawa, G Salanti, A Chaimani, L Atkinson, Y Ogawa, S Leucht, H Ruhe, E Turner, J Higgins, M Egger, N Takeshima, Y Hayasaka, H Imai, K Shinohara, A Tajika, J Ioannidis, J Geddes

The Lancet , 2018

Background Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder. Methods We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291. Findings We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89–2·41) for amitriptyline and 1·37 (1·16–1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72–0·97) and fluoxetine (0·88, 0·80–0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01–1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19–1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51–0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43–0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30–2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low. Interpretation All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants. Funding National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.

The Hamilton Depression Rating Scale is a tool used to measure the severity of depression before, during and after treatment. It consists of 17 questions about symptoms and signs of depression. A score of 14 to 18 is classed as moderate depression, and 19 to 22 severe depression. The average baseline severity score in these trials was high at 25.7.

Expert commentary

Antidepressants are helpful for many – but with group differences regarding acceptability, side effects and recovery. However, not everyone wants medication or can tolerate them, and a proportion fail to recover or improve.

Tablets don’t directly address important external or internal challenges (e.g. relationships or debt). Talking therapies can be effective – but also may not be wanted, adhered to or tolerated. Maximal response is likely to be individualised, selecting appropriate psychological, biological and social interventions that the individual wishes to use, and which lead to recovery.

Varied evidence-based treatments should be available based on individual wishes, tolerability and impact.

Chris Williams, Emeritus Professor of Psychosocial Psychiatry and President of the British Association for Behavioural and Cognitive Psychotherapies (BABCP), University of Glasgow, and Director Five Areas Ltd

Expert commentary

This is an important and comprehensive look at all the evidence on the clinical efficacy of antidepressants. It confirms that antidepressants can be effective though leaves some questions unanswered.

We still don't know whether the patients now receiving antidepressants in UK primary care are benefiting from antidepressants as many of these trials are very old and carried out for regulatory purposes rather than to inform clinical practice in the NHS. The trials also looked at short-term outcomes up to about eight weeks.

We still don't know about the long-term benefits (or harms) of antidepressants. It's a cliché, but further research is needed.

Glyn Lewis, Professor of Psychiatric Epidemiology, UCL Division of Psychiatry