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Cited by 167Treatment of Major DepressionMental Health Treatment and AccessPsychological Treatments and Disorders

Should antidepressants be used for major depressive disorder?

Open access
Jakobsen, Janus Christian, Gluud, Christian, Kirsch, Irving·2020·BMJ Evidence-Based Medicine
DOI 10.1136/bmjebm-2019-111238PMC PMC7418603
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Abstract

Background: Major depressive disorder is estimated by the WHO to affect more than 300 million people globally, making depression the leading cause of disability worldwide. Antidepressants are commonly used to treat depression. Objective: The study aimed to provide an update on the evidence on the effects of antidepressants compared with placebo. Should antidepressants be used for adults with major depressive disorder? Study selection: We searched the Cochrane Library, BMJ Best Practice and PubMed up to June 2019 with the search terms ‘depression’ and ‘antidepressants’ targeting reviews published in English since 1990. Findings: Several reviews have assessed the effects of antidepressants compared with placebo for depression. Generally, all the previous reviews show that antidepressants seem to have statistically significant effects on depressive symptoms, but the size of the effect has questionable importance to most patients. Antidepressants seem to have minimal beneficial effects on depressive symptoms and increase the risk of both serious and non-serious adverse events. Conclusions: The benefits of antidepressants seem to be minimal and possibly without any importance to the average patient with major depressive disorder. Antidepressants should not be used for adults with major depressive disorder before valid evidence has shown that the potential beneficial effects outweigh the harmful effects.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review argues that antidepressants for adults with major depressive disorder produce statistically significant but clinically minimal symptom reductions and increase adverse events, so benefits may not outweigh harms. The authors conclude antidepressants should not be used for major depressive disorder until valid evidence shows net benefit.

Key findings

  • Across reviews, antidepressants versus placebo show statistically significant effects on depressive symptoms, but effect sizes are below clinical significance thresholds. In the authors’ 2017 systematic review, SSRIs versus placebo reduced HDRS by 1.94 points (95% CI −2.50 to −1.37) or SMD −0.23 (95% CI −0.31 to −0.14), below NICE’s 3-point/0.5 SMD threshold and far from a 7-point HDRS/0.875 SMD “minimal improvement.”
  • A large network meta-analysis found overall antidepressants versus placebo SMD 0.30 (95% credibility interval 0.26 to 0.34), which the authors call presumably without clinical relevance; only 18% of included trials were assessed at low risk of bias.
  • SSRIs significantly increased the risk of both serious and non-serious adverse events; common long-term adverse effects include gastrointestinal problems, sleep disturbances, and sexual dysfunction, and withdrawal symptoms can persist more than 2 weeks and sometimes several months. Longer-term effects (SMD 0.34) and NICE results (SMD 0.28) seemed as small as short-term effects.
  • Industry involvement and bias were prominent: industry-sponsored studies more often showed benefits (RR 1.27, 95% CI 1.17 to 1.37) and favorable conclusions (RR 1.34, 95% CI 1.19 to 1.51), and meta-analyses with a manufacturer-employed author were 22-fold less likely to have negative statements. In STAR*D, 77.8% of patients would have been excluded from conventional trials, with HDRS improvement of 6.6 points after 3 months of SSRI treatment versus 14.8 points in conventional comparator trials.

Methods

  • Narrative review: two investigators independently searched the Cochrane Library, BMJ Best Practice, and PubMed up to June 2019 for English reviews published since 1990 using the terms “depression” and “antidepressants”; they included any review assessing benefits and harms of any antidepressant versus placebo in adults, plus references and relevant guideline recommendations.
  • No protocol was published before the literature search. The synthesis is narrative rather than systematic, and it focuses on adults with a primary diagnosis of major depressive disorder, excluding primary somatic disorders or other disorders.
  • Main analysis is a narrative synthesis of identified reviews, with attention to clinical significance thresholds, risk of bias, industry involvement, and harms.

Limitations

  • Stated: no protocol was published before the literature search; the majority of previous antidepressant trials were at high or unclear risk of bias; evidence has low generalisability because trials include highly selected patients; short-term trials likely underestimate adverse effects; the HDRS is psychometrically and conceptually flawed; and no studies clearly identify who will respond to antidepressants.
  • Stated: the authors’ GRADE assessment of the certainty of evidence was very low certainty.
  • Evident: as a narrative review without a protocol or systematic meta-analysis, selection and interpretation of included reviews may be susceptible to bias, and the paper relies on existing reviews rather than new primary data.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1136/bmjebm-2019-111238

Cites

67 of 67 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 96 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Antidepressants have statistically significant effects on depressive symptoms.

    “Generally, all the previous reviews show that antidepressants seem to have statistically significant effects on depressive symptoms”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] source

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  • Findingnone given

    We have not identified any studies that identify clearly who will respond to antidepressants and who will not.

    “Moreover, we have not identified any studies that identify clearly who will respond to antidepressants and who will not.”
    Quote in the paperNot a substantial claim
  • Findingown data

    The few trials assessing long-term effects showed that such effects seemed even smaller than the short-term effects.

    “The few trials assessing long-term effects showed that such effects seemed even smaller than the short-term effects.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Jakobsen, 2017, Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and trial sequential analysis, BMC Psychiatr source

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  • Findingcitation

    All previous reviews show that antidepressants have statistically significant effects on depressive symptoms.

    “All these previous reviews show that antidepressants have statistically significant effects on depressive symptoms.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] source

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  • Findingcitation

    In the 2017 systematic review, SSRIs compared with placebo had a statistically significant effect on depressive symptoms.

    “That review found, as all other previous reviews have shown, that SSRIs compared with placebo had a statistically significant effect on depressive symptoms.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Jakobsen, 2017, Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and trial sequential analysis, BMC Psychiatr source

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  • May combine two claims. 33
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Findingcitation

    SSRIs significantly increase the risk of both serious and non-serious adverse events compared with placebo.

    “We found that SSRIs significantly increased the risk of both serious and non-serious adverse events.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Jakobsen, 2017, Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and trial sequential analysis, BMC Psychiatr source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    The vast majority of previous reviews were non-systematic narrative reviews.

    “The vast majority of the previous reviews were non-systematic reviews (according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)), that is, narrative reviews.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Liberati, 2009, The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration, BMJ source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Findingnone given

    Several other reviews have been published generally confirming that antidepressants have statistically significant effects, but only a few of these reviews assessed the clinical significance of the review results.

    “As mentioned, several other reviews have been published generally confirming that antidepressants have statistically significant effects, but only a few of these reviews assessed the clinical significance of the review results.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    That review found no significant effect of SSRIs on the HDRS in trials at low risk of 'for profit' bias, whereas the beneficial effects were statistically significant in trials at high or unclear risk of 'for profit' bias.

    “That review found no significant effect of SSRIs on the HDRS in trials at low risk of ‘for profit’ bias, whereas the beneficial effects were statistically significant in trials at high or unclear risk of ‘for profit’ bias.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Jakobsen, 2017, Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and trial sequential analysis, BMC Psychiatr source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    One small individual patient data meta-analysis found support for increasing benefit with increasing severity of depression, but three larger individual patient data meta-analyses did not find any such effect of antidepressants compared with placebo on depression severity.

    “One small individual patient data meta-analysis found support for increasing benefit with increasing severity of depression,20 but three larger individual patient data meta-analyses did not find any such effect of antidepressants compared with placebo on depression severity .44–46”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [20] source

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    • cites [44] source

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    • cites [45] source

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    • cites [46] source

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  • May combine two claims.

    Findingcitation

    Other studies have found support for increasing benefit with increasing severity of depression, but the effect size even for patients with the most severe depression was still minimal.

    “Other studies have found support for increasing benefit with increasing severity of depression,21 but the effects size even for patients with the most severe depression was still minimal.21”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Kirsch, 2008, Initial severity and antidepressant benefits: a meta-analysis of data submitted to the food and drug administration, PLoS Med source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    NICE previously suggested that a three-point difference on the HDRS or a 0.5 SMD met the criteria for clinical significance (minimally important difference).

    “NICE previously suggested that a three-point difference on the HDRS or a 0.5 standardised mean difference (SMD) met the criteria for clinical significance (minimally important difference).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] National Institute for Clinical Excellence . Depression: management of depression. primary and secondary care clinical practice guideline no 23 London: NICE, 2004. Available: wwwniceorguk/pageaspx?o=235213

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A person who improves by ≥50% is called a responder, whereas one who improves by 49% is called a non-responder, thus inflating the apparent difference between these patients.

    “Furthermore, a person who improves by ≥50% is called a responder, whereas one who improves by 49% is called a non-responder, thus inflating the apparent difference between these patients.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The diagnosis of major depressive disorder in clinical practice is based on the presence of certain symptoms according to DSM-5 or ICD-10.

    “The diagnosis of major depressive disorder in clinical practice is based on the presence of certain symptoms according to the diagnostic criteria outlined in either the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) or the International Classification of Diseases-10th Revision.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] WHO . The ICD-10 classification of mental and behavioral disorders: clinical descriptions and diagnostic guidelines. Available: http://www.who.int/classifications/icd/en/bluebook.pdf [Accessed Mar 2018].

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    • cites [5] American Psychiatric Association . Practice guideline for the treatment of patients with major depressive disorder. 3rd edn, 2010.

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The NICE thresholds for clinical significance were not empirically based and are presumably too small.

    “The above-mentioned thresholds suggested by NICE were not empirically based and are presumably too small.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] source

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  • May combine two claims.

    Interpretationcitation

    A difference of, for example, two HDRS points must be regarded as a minimal effect and is presumably undetectable by the average patient with depression.

    “all available evidence shows that a difference of, for example, two HDRS points must be regarded as a minimal effect and is presumably undetectable by the average patient with depression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] source

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  • May combine two claims.

    Premisecitation

    When other assessment scales are used (eg, Beck Depression Inventory, Montgomery-Åsberg Depression Rating Scale, Hamilton six-item scale), the results correspond to the HDRS results, that is, statistically significant results with questionable importance to the average patient.

    “It must also be noted that when other assessment scales are used (eg, Beck Depression Inventory, Montgomery-Åsberg Depression Rating Scale, Hamilton six-item scale), the results correspond to the HDRS results, that is, statistically significant results with questionable importance to the average patient.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Jakobsen, 2017, Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and trial sequential analysis, BMC Psychiatr source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The effect size of SSRIs was below the predefined threshold for clinical significance and far from 'minimal improvement'.

    “was, however, below the predefined threshold for clinical significance (the above-mentioned NICE criteria) and far from ‘minimal improvement’ (eg, seven-point change on the HDRS or an SMD of 0.875).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Jakobsen, 2017, Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and trial sequential analysis, BMC Psychiatr source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    There is a great risk that the results of the 2017 review overestimate the beneficial effects and underestimate the harmful effects of SSRIs.

    “so there is a great risk that the results of the review overestimate the beneficial effects and underestimate the harmful effects of SSRIs.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [32] source

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    • cites [33] source

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    • cites [34] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The review did not have a published protocol before performing the literature search.

    “We have not published a protocol before performing the literature search, which is a limitation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation

    Neither serious nor non-serious adverse events were assessed in the network meta-analysis.

    “Neither serious nor non-serious adverse events were assessed in the network meta-analysis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Cipriani, 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, The Lancet source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    These empirically derived thresholds do not necessarily provide a precise estimate of what patients consider the smallest worthwhile effect of antidepressants.

    “It should, however, be noted that these empirically derived thresholds do not necessarily provide a precise estimate of what patients consider the smallest worthwhile effect of antidepressants.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The benefits of antidepressants are minimal and possibly without any importance to the average patient with major depressive disorder.

    “The benefits of antidepressants seem to be minimal and possibly without any importance to the average patient with major depressive disorder.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    When assessing dichotomised outcomes, there is a considerable risk of overestimating benefit, but there is also a risk of not detecting a 'true' effect.

    “Hence, when assessing such dichotomised outcomes, there is a considerable risk of overestimating benefit, but there is also a risk of not detecting a ‘true’ effect.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisereasoning

    A person who improves by ≥50% is categorised as being the same as a person whose symptoms disappear completely, and one with 49% improvement is considered the same as a person showing no improvement at all.

    “Conversely, a person who improves by ≥50% is categorised as being the same as a person whose symptoms disappear completely, and one with 49% improvement is considered the same as a person showing no improvement at all.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    It may be argued that it is not even possible to assess the clinical relevance of a given HDRS score, and that the evidence base is thus fundamentally flawed due to the reliance on the HDRS.

    “Consequently, it may be argued that it is not even possible to assess the clinical relevance of a given HDRS score, and that the evidence base is thus fundamentally flawed due to the reliance on the HDRS.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    Due to easily recognised adverse events in the experimental group and lack of adverse effects in the control groups, some patients might be able to figure out if they received an antidepressant or a placebo, which might compromise blinding and hence valid assessment of subjective symptoms.

    “Even if the trials used matching placebo, due to easily recognised adverse events in the experimental group and lack of adverse effect in the control groups, some patients might be able to figure out if they received an antidepressant or a placebo, which might compromise blinding and hence valid assessment of subjective symptoms.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    As a substantial proportion of research concerning antidepressants is prone to 'for profit bias', the results of previous results likely overestimate benefit and underestimate harm.

    “As a substantial proportion of research concerning antidepressants is prone to ‘for profit bias’, the results of previous results likely overestimate benefit and underestimate harm.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [30] source

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    • cites [39] Lundh A , Lexchin J , Mintzes B , et al . Industry sponsorship and research outcome. Cochrane Database Syst Rev 2017;2.doi:10.1002/14651858.MR000033.pub3 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Even though there is no valid evidence showing beneficial effects of antidepressants for depression, we cannot exclude that the evidence is showing beneficial effects for other conditions than major depressive disorder.

    “Even though there is no valid evidence showing beneficial effects of antidepressants for depression, we cannot exclude that the evidence is showing beneficial effects for other conditions than major depressive disorder.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Industry-sponsored studies showed more often benefits (RR 1.27, 95% CI 1.17 to 1.37) and more often favourable conclusions (RR 1.34, 95% CI 1.19 to 1.51).

    “Industry-sponsored studies showed more often benefits, relative risk (RR) 1.27 (95% CI 1.17 to 1.37), and more often favourable conclusions, RR 1.34 (95% CI 1.19 to 1.51).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [39] Lundh A , Lexchin J , Mintzes B , et al . Industry sponsorship and research outcome. Cochrane Database Syst Rev 2017;2.doi:10.1002/14651858.MR000033.pub3 source

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  • May combine two claims.

    Interpretationreasoning

    Despite biases inflating beneficial effects of review results, they still show only negligible differences between antidepressants and placebo on depressive symptoms, and the 'true' effect of antidepressants might not even be statistically significant.

    “Despite biases inflating beneficial effects of review results, they still show only negligible differences between antidepressants and placebo on depressive symptoms, and the ‘true’ effect of antidepressants might not even be statistically significant.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    There is a great risk that the results of the network meta-analysis overestimate the beneficial effects and underestimate the harmful effects of antidepressants.

    “so there is a great risk that the results of the review overestimate the beneficial effects and underestimate the harmful effects of antidepressants.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [32] source

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    • cites [33] source

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    • cites [34] source

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  • May combine two claims.

    Interpretationreasoning

    If the effect estimates from previous reviews are related to the NICE criteria, then the previous reviews confirm that antidepressants generally have minimal beneficial effects on depressive symptoms.

    “Nevertheless, if the effect estimates from the previous reviews are related to, for example, the NICE criteria (see ‘How much difference should antidepressants make?’ section), then the previous reviews confirm that antidepressants generally have minimal beneficial effects on depressive symptoms.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Trials at high or unclear risk of bias tend to overestimate benefits and underestimate harms.

    “Trials at high or unclear risk of bias tend to overestimate benefits and underestimate harms.”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [30] source

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    • cites [32] source

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    • cites [36] source

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    • cites [37] Hróbjartsson, 2012, Observer bias in randomised clinical trials with binary outcomes: systematic review of trials with both blinded and non-blinded outcome assessors, BMJ source

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    • cites [38] source

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    • cites [39] Lundh A , Lexchin J , Mintzes B , et al . Industry sponsorship and research outcome. Cochrane Database Syst Rev 2017;2.doi:10.1002/14651858.MR000033.pub3 source

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    • cites [40] Nüesch E , Trelle S , Reichenbach S , et al . The effects of excluding patients from the analysis in randomised controlled trials: meta-epidemiological study. BMJ 2009;339.doi:10.1136/bmj.b3244 source

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    • cites [41] source

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  • Classified as probably not a substantial claim.

    Interpretationcitation

    Such an effect size (SMD 0.30) is presumably without any clinical relevance.

    “Such an effect size is presumably without any clinical relevance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Moncrieff, 2015, Empirically derived criteria cast doubt on the clinical significance of antidepressant-placebo differences, Cont Clin Trials source

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  • May combine two claims.

    Interpretationreasoning

    These data indicate that, in a clinical setting, the benefit of antidepressants is low and that the exclusion criteria typically used in randomised clinical trials lead to inflated effect estimates.

    “These data indicate that, in a clinical setting, the benefit of antidepressants is low and that the exclusion criteria typically used in randomised clinical trials lead to inflated effect estimates.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The effect of adding antidepressants to psychotherapy was minimal and below the NICE criteria.

    “A non-systematic review showed that adding antidepressants to psychotherapy seemed to have a statistically significant effect, but again the effect was minimal and below the NICE criteria (SMD 0.35; 95% CI 0.24 to 0.45; p<0.001).10”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] source

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  • May combine two claims.

    Interpretationreasoning

    The effects of adding antidepressants to psychotherapy seem negligible just as the effects of antidepressants when used as the only therapy.

    “The effects of adding antidepressants to psychotherapy seem negligible just as the effects of antidepressants when used as the only therapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    For SSRIs, the increased relative risk of a serious adverse event is quite large, but the absolute risk of a serious adverse event is still small, while SSRI adverse events not considered severe are more common.

    “Even though the increased relative risk of a serious adverse event is quite large, the absolute risk of a serious adverse event is still small, while SSRI adverse events not considered severe are more common.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Jakobsen, 2017, Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and trial sequential analysis, BMC Psychiatr source

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  • Classified as probably not a substantial claim.

    Premisecitation

    Adding antidepressants to psychotherapy seemed to have a statistically significant effect (SMD 0.35; 95% CI 0.24 to 0.45; p<0.001).

    “A non-systematic review showed that adding antidepressants to psychotherapy seemed to have a statistically significant effect, but again the effect was minimal and below the NICE criteria (SMD 0.35; 95% CI 0.24 to 0.45; p<0.001).10”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] source

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  • May combine two claims.

    Premisecitation

    SSRIs increase the risk of both serious and non-serious adverse events.

    “It has been shown that SSRIs, the most commonly used antidepressants, increase the risk of both serious and non-serious adverse events.28”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Jakobsen, 2017, Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and trial sequential analysis, BMC Psychiatr source

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  • May combine two claims.

    Interpretationreasoning

    Withdrawal symptoms might explain why some studies have alleged to show that the risk of relapse seems to be reduced if antidepressants are continued instead of not continued, and might be the reason why patients who do not continue antidepressants might do worse compared with patients who continue antidepressants.

    “Withdrawal symptoms might also explain why some studies have alleged to show that the risk of relapse seems to be reduced if antidepressants are continued instead of not continued.54 55”
    • Also stated in: § Withdrawal symptoms · hedged
      “Withdrawal symptoms might be the reason why patients who do not continue antidepressants might do worse compared with patients who continue antidepressants.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [54] source

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    • cites [55] Reid, 2010, Long term treatment of depression with selective serotonin reuptake inhibitors and newer antidepressants, BMJ source

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  • May combine two claims.

    Premisecitation

    Withdrawal symptoms after SSRIs typically occur within a few days from drug discontinuation and last a few weeks, also with gradual tapering.

    “Withdrawal symptoms after SSRIs typically occur within a few days from drug discontinuation and last a few weeks, also with gradual tapering”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] source

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  • May combine two claims.

    Premisecitation

    TCAs can cause seizures as well as death due to the slowing of intraventricular conduction, leading to complete heart block or ventricular arrhythmias.

    “Non-randomised studies have, for example, shown that TCAs can cause seizures as well as death due to the slowing of intraventricular conduction, leading to complete heart block or ventricular arrhythmias.49”
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    • cites [49] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Antidepressants in combination with psychotherapy are recommended for major depressive disorder by both NICE and the American Psychiatric Association, as well as other guidelines.

    “Antidepressants in combination with psychotherapy are recommended for major depressive disorder by both NICE and the American Psychiatric Association, as well as other guidelines.5 13 14 16 56 57”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [5] American Psychiatric Association . Practice guideline for the treatment of patients with major depressive disorder. 3rd edn, 2010.

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    • cites [13] source

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    • cites [14] Gelenberg AJ , Freeman MP , Markowitz JC , et al . Practice guideline for the treatment of patients with major depressive disorder. 3rd edn. American Psychiatric Association, 2010.

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    International guidelines, as a first step, recommend sleep hygiene institution and implementing lifestyle changes, such as adopting regular exercise, smoking cessation and a healthy diet, tapering of drugs that can lower mood, and addressing substance use if relevant.

    “International guidelines, as a first step, recommend sleep hygiene institution and implementing lifestyle changes, such as adopting regular exercise,14 16 smoking cessation and a healthy diet,14 16 tapering of drugs that can lower mood, and addressing substance use if relevant16”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Gelenberg AJ , Freeman MP , Markowitz JC , et al . Practice guideline for the treatment of patients with major depressive disorder. 3rd edn. American Psychiatric Association, 2010.

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    • cites [16] source

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41 of 41

  • The paper relies on this without support.

    The DSM-5 and ICD-10 diagnostic criteria for major depressive disorder are largely comparable.

    “These two sets of diagnostic criteria are largely comparable.”

  • The paper relies on this without support.

    There are no objective tests or laboratory tests for depression or for validating the diagnosis.

    “There are no objective tests and no laboratory test (eg, blood tests, MRI scans) for depression or for validating the diagnosis.”

  • The paper relies on this without support.

    The HDRS is the most commonly used depression rating scale and is recommended by psychiatrists worldwide.

    “The HDRS is the most commonly used depression rating scale and is the recommended scale by psychiatrists worldwide.”

  • The paper relies on this without support.

    Theoretically and in clinical practice, some patients might benefit significantly from antidepressants.

    “theoretically and in clinical practice some patients might benefit significantly from antidepressants.”

  • The paper relies on this without support.

    Adverse effects of other types of antidepressant than SSRIs are not thoroughly assessed in systematic reviews.

    “Adverse effects of other types of antidepressant than SSRIs (eg, serotonin-norepinephrine reuptake inhibitors and tricyclic antidepressants (TCAs)) are not thoroughly assessed in systematic reviews”
5 of 5

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Authors
Jakobsen, J. C., Gluud, C., & Kirsch, I.
Affiliations
  • University of Southern Denmark (DK)
  • Copenhagen University Hospital (DK)
  • Harvard University (US)
Corresponding author
Jakobsen, Janus Christian
ORCID
Venue
BMJ Evidence-Based Medicine
Publisher
BMJ
Published
2019-09-25
Volume
25
Issue
4
Pages
130-130
ISSN
  • 1356-5524 (ISSN-L)
  • 2515-446X
  • 2515-4478
DOI
10.1136/bmjebm-2019-111238
PMC
PMC7418603
OpenAlex
W2976089272
Semantic Scholar
c4a6ec1e247c44823d725a842af2cf3753519d60
Cited by
162
References
67
Citations by year
2026: 13 · 2025: 28 · 2024: 21 · 2023: 38 · 2022: 22 · 2021: 24 · 2020: 14 · 2019: 2
FWCI
1.99
Type
journal article
Language
en
Open access
Licence
Locations
  • BMJ Evidence-Based Medicine (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, cc-by-nc)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Social Sciences › Psychology › Social Psychology › Mental Health Treatment and Access
  • Social Sciences › Psychology › Clinical Psychology › Psychological Treatments and Disorders
Keywords
antidepressants, major depressive disorder, depression, antidepressant efficacy, antidepressant side effects, placebo comparison, risk-benefit assessment, treatment decision-making
MeSH terms
Antidepressive Agents, Depressive Disorder, Major, Major Depressive Disorder, Humans, Treatment Outcome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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