Depression Käypä hoito -suosituksen lähdekritiikkiä

Aina sitä ei jaksa ruveta tarkistamaan kaikkia viitteitä, joiden perusteella jotakin väitetään lääketieteellisissä kirjoituksissa. Luin Duodecimin Masennuksen Käypä hoito-suosituksesta seuraavan väitteen:

”Noin kaksi kolmasosaa masennuslääkettä säännöllisesti käyttävistä saa selvän vasteen ja noin 40-50%:lla oireet häviävät melko täydellisesti noin 6-8 viikon aikana.”

Minä jäin pohtimaan, että mistä ihmeestä suosituksen laatijat ovat näin yltiöpositiivisia lukuja löytäneet. Katsoin tarkemmin. Väitteen tueksi oli listattu peräti 10 tieteellistä artikkelia (viitteet 92-102), joiden perusteella näytön aste oli arvioitu vahvaksi.

Päätin tarkistaa viitteet. Löysin netistä kaikki kymmenen artikkelia ja luin huolella jokaisen artikkelin yhteenvedon ja johtopäätökset. Yllätyksekseni jouduin toteamaan, että yksikään näistä kymmenestä artikkelista ei puhunut väitteen puolesta, jotkut eivät liittyneet aiheeseen mitenkään ja jotkut puhuivat vastakkaista kieltä. Katso itse jos jaksat.

92. Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy. Turner EH ym. N Engl J Med 2008;358:252-60.  

We cannot determine whether the bias observed resulted from a failure to submit manuscripts on the part of authors and sponsors, from decisions by journal editors and reviewers not to publish, or both. Selective reporting of clinical trial results may have adverse consequences for researchers, study participants, health care professionals, and patients.

93. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. Kirsch I ym. PLoS Med 2008;5:e45. 

Drug-placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.

94. A regulatory Apologia–a review of placebo-controlled studies in regulatory submissions of new-generation antidepressants. Melander H ym. Eur Neuropsychopharmacol 2008;18:623-7

Data on percentage of patients experiencing a relevant response (>50% reduction of the baseline Hamilton Depression Scale (HAMD) score), average baseline severity and sample size were retrieved for all placebo-controlled studies in regulatory submissions of SSRIs and SNRIs between 1984 and 2003. Overall there was 16%-units (95% CI: 12; 20) more responders on active drug compared to placebo. There was no evidence of a diminishing magnitude of effect with lower severity at baseline. With one exception, significant differences varying between 13.5 and 19.3%-units were demonstrated for the individual antidepressants. Statistically significant mean differences versus placebo in change in HAMD are not a proper basis for evaluation of clinical relevance and are not sufficient for approval. Differences in the percentage of patients experiencing a clinically relevant response should also be demonstrated. In this respect, the approved SSRIs and SNRIs were found superior to placebo, independent of severity of depression.

95. Antidepressant drug effects and depression severity: a patient-level meta-analysis. Fournier JC ym. JAMA 2010;303:47-53

The magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial.

96. Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials. Eyding D ym. BMJ 2010;341:c4737

Reboxetine is, overall, an ineffective and potentially harmful antidepressant. Published evidence is affected by publication bias, underlining the urgent need for mandatory publication of trial data.

97. Efficacy of antidepressants for dysthymia: a meta-analysis of placebo-controlled randomized trials. Levkovitz Y ym. J Clin Psychiatry 2011;72:509-14

These results support the utility of antidepressants for dysthymic disorder. In fact, the margin of efficacy of antidepressants for dysthymic disorder was larger than for MDD. Future studies providing longer-term data on the treatment of dysthymic disorder with antidepressants are essential.

98. Randomized, placebo-controlled trials of antidepressants for acute major depression: thirty-year meta-analytic review. Undurraga J ym. Neuropsychopharmacology 2012;37:851-64

Abstract: Antidepressant-placebo response-differences (RDs) in controlled trials have been declining, potentially confounding comparisons among older and newer drugs. For clinically employed antidepressants, we carried out a meta-analytic review of placebo-controlled trials in acute, unipolar, major depressive episodes reported over the past three decades to compare efficacy (drug-placebo RDs) of individual antidepressants and classes, and to consider factors associated with year-of-reporting by bivariate and multivariate regression modelling. Observed drug-placebo differences were moderate and generally similar among specific drugs, but larger among older antidepressants, notably tricyclics, than most newer agents. This outcome parallels selective increases in placebo-associated responses as trial-size has increased in recent years. Study findings generally support moderate efficacy of clinically employed antidepressants for acute major depression, but underscore limitations of meta-analyses of controlled trials for ranking drugs by efficacy. We suggest that efficiency and drug-placebo differences may be improved with fewer sites and subjects, and better quality-control of diagnostic and clinical assessments.

99. Benefits from antidepressants: synthesis of 6-week patient-level outcomes from double-blind placebo-controlled randomized trials of fluoxetine and venlafaxine. Gibbons RD ym. Arch Gen Psychiatry 2012;69:572-9

To our knowledge, this is the first research synthesis in this area to use complete longitudinal person-level data from a large set of published and unpublished studies. The results do not support previous findings that antidepressants show little benefit except for severe depression. The antidepressants fluoxetine and venlafaxine are efficacious for major depressive disorder in all age groups, although more so in youths and adults compared with geriatric patients. Baseline severity was not significantly related to degree of treatment advantage over placebo.

100. Antidepressant efficacy of agomelatine: meta-analysis of published and unpublished studies. Taylor D ym. BMJ 2014;348:g1888

Agomelatine is an effective antidepressant with similar efficacy to standard antidepressants. Published trials generally had more favourable results than unpublished studies.

101. Vortioxetine: a meta-analysis of 12 short-term, randomized, placebo-controlled clinical trials for the treatment of major depressive disorder. Pae CU ym. J Psychiatry Neurosci 2015;40:174-86

Although our results suggest that vortioxetine may be an effective treatment option for MDD, they should be interpreted and translated into clinical practice with caution, as the meta-analysis was based on a limited number of heterogeneous RCTs.

102. Systematic Review and Meta-Analysis: Dose-Response Relationship of Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder. Jakubovski E ym. Am J Psychiatry 2016;173:174-83

Higher doses of SSRIs appear slightly more effective in major depressive disorder. This benefit appears to plateau at around 250 mg of imipramine equivalents (50 mg of fluoxetine). The slightly increased benefits of SSRIs at higher doses are somewhat offset by decreased tolerability at high doses.