Examining the antidepressant scattergun approach
Authors: Brenda Penninx
Journal: The Lancet Psychiatry (2019)

Antidepressants are often seen in a negative light, which is unfortunate as the efficacy of such drugs has been indicated for both major depressive disorder and generalised anxiety disorder in recent network meta-analyses.1Cipriani 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: 1357-1366Summary Full Text Full Text PDF PubMed Scopus (1335) Google Scholar, 2Slee A Nazareth I Bondaronek P Liu Y Cheng Z Freemantle N Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis.Lancet. 2019; 393: 768-777Summary Full Text Full Text PDF PubMed Scopus (125) Google Scholar The statistically significant but small effect size of antidepressants has been described as not very different from that of many common medications.3Leucht S Helfer B Gartlehner G Davis JM How effective are common medications: a perspective based on meta-analyses of major drugs.BMC Med. 2015; 13: 253Crossref PubMed Scopus (57) Google Scholar Therefore, antidepressants are an important tool in reducing the burden of the most common mental disorders. Such tools are necessary, as depression and anxiety disorders are widespread, have huge public health burden, and do not always get the medical attention they deserve. Unfortunately, antidepressants are not magic pills—they do not work for everyone. About 30–50% of patients with depression or anxiety do not respond adequately to antidepressants. Therefore, much research is focused on developing alternative treatments and trying to predict more accurately for which patients antidepressants will work. The intention of this precision medicine research is to find a stricter, better defined population that clearly benefits from antidepressants, thereby reducing unnecessary use. In The Lancet Psychiatry, Gemma Lewis and colleagues report the results of the PANDA trial,4Lewis G Duffy L Ades A et al.The clinical effectiveness of sertraline in primary care and the role of depression severity and duration: a pragmatic, double-blind, placebo-controlled randomised trial.Lancet Psychiatry. 2019; (published online Sept 19)https://doi.org/10.1016/S2215-0366(19)30366-9Scopus (55) Google Scholar which takes the opposite approach. This trial examined whether antidepressants are effective in a larger, broader, and more vaguely defined primary care population. This is an important research question, as primary care is the largest treatment setting for depression and anxiety. In contrast to most earlier antidepressant trials, which included strictly defined patient groups, antidepressant prescription in primary care often occurs without standardised assessment of diagnoses or symptoms and to a patient group that is widely variable in their duration and severity of symptoms. This placebo-controlled trial was not funded by the pharmaceutical industry, was large (with 655 randomly assigned participants), and consisted of a population for which there was clinical uncertainty whether an antidepressant should be prescribed. It should be noted that some of the participants were recruited by review of clinical records, but were not per se current patients or treatment seekers at that moment, thereby limiting the generalisability to usual practice. Nevertheless, the results of the PANDA trial are interesting. The effect of sertraline on depressive symptom reduction within 6 weeks (primary outcome) was not significant (mean 6-week Patient Health Questionnaire, 9-item version [PHQ-9] score 7·98 [SD 5·63] in the sertraline group and 8·76 [5·86] in the placebo group; adjusted proportional difference 0·95, 95% CI 0·85–1·07; p=0·41), but there was a mild depressive effect over 12 weeks (group by time interaction for Beck Depression Inventory-II p=0·015 and for PHQ-9 p=0·0905. Larger effects of sertraline versus placebo were observed for the secondary outcomes of general anxiety symptoms, functioning, and self-reported mental health over both 6 weeks and 12 weeks of follow-up. What important lessons does this pragmatic trial teach us? The trial indicates that the beneficial effect of antidepressants on anxiety symptoms is larger than the effect on depressive symptoms. It also shows that antidepressants might be of benefit to a wider group of patients than previously thought, including those with mild to moderate symptoms who do not meet diagnostic criteria for depression or generalised anxiety disorder. Therefore, this large-scale study adds important information to earlier systematic reviews that were not able to confirm significant effectiveness of antidepressants in subthreshold or mild depression.5Barbui C Cipriani A Patel V Ayuso-Mateos JL van Ommeren M Efficacy of antidepressants and benzodiazepines in minor depression: systematic review and meta-analysis.Br J Psychiatry. 2011; 198: 11-16Crossref PubMed Scopus (153) Google Scholar, 6Cameron IM Reid IC MacGillivray SA Efficacy and tolerability of antidepressants for sub-threshold depression and for mild major depressive disorder.J Affect Disord. 2014; 166: 48-58Crossref PubMed Scopus (24) Google Scholar Should we apply a bigger scattergun approach to antidepressants? The PANDA trial shows that antidepressants are effective in primary care and suggests that there is a larger population than only those with established diagnoses that could benefit from them. Nevertheless, there are also reasons to be cautious in too easily prescribing antidepressants. First, overall effect sizes found in the PANDA trial were small and longer-term effects of antidepressants were not examined. There was no significant interaction with severity observed for the effectiveness of antidepressants, but as the authors adequately point out, their statistical power to test an interaction was restricted. Therefore, lower effectiveness of sertraline in patients with milder symptoms cannot be ruled out. Second, although pharmacological treatment is often the first choice for clinicians because of low cost and no resource constraints, psychological alternatives are available and have been shown to be equally effective.7Weitz ES Hollon SD Twisk J et al.Baseline depression severity as moderator of depression outcomes between cognitive behavioral therapy vs pharmacotherapy: an individual patient data meta-analysis.JAMA Psychiatry. 2015; 72: 1102-1109Crossref PubMed Scopus (118) Google Scholar Many primary care patients seem to prefer psychotherapy over pharmacotherapy.8Prins MA Verhaak PF van der Meer K Penninx BW Bensing JM Primary care patients with anxiety and depression: need for care from the patient's perspective.J Affect Disord. 2009; 119: 163-171Crossref PubMed Scopus (43) Google Scholar Having various treatment options available remains important to tackle the burden of common mental disorders. Third, the growing group of antidepressant users in the last decade is, in part, due to the growing group of long-term users. Placebo-controlled trials showed that antidepressant maintenance after remission reduces relapse risk compared with placebo.9Borges S Chen YF Laughren TP et al.Review of maintenance trials for major depressive disorder: a 25-year perspective from the US Food and Drug Administration.J Clin Psychiatry. 2014; 75: 205-214Crossref PubMed Google Scholar Consequently, treatment guidelines now state that antidepressant use should be continued until 4–6 months after remission, after which discontinuation should be considered. However, the reality is that many patients often continue their antidepressants for months or even years after symptom remission. Unfortunately, disturbing side-effects such as sexual dysfunction, emotional flattening, dry mouth, headache, weight gain, and metabolic dysregulation remain after long-term use.10Bet PM Hugtenburg JG Penninx BW Hoogendijk WJ Side effects of antidepressants during long-term use in a naturalistic setting.Eur Neuropsychopharmacol. 2013; 23: 1443-1451Crossref PubMed Scopus (145) Google Scholar Long-term antidepressant use also increases medicalisation, contrasts with patient wishes, and contributes to a reduced sense of recovery. In the process of pharmacotherapy, antidepressant discontinuation deserves as much clinical attention as antidepressant initiation. I declare grants from the Dutch Ministry of Health/NWO (ZonMw), Boehringer Ingelheim, and Jansen Research, in relation to the work discussed here. The clinical effectiveness of sertraline in primary care and the role of depression severity and duration (PANDA): a pragmatic, double-blind, placebo-controlled randomised trialSertraline is unlikely to reduce depressive symptoms within 6 weeks in primary care but we observed improvements in anxiety, quality of life, and self-rated mental health, which are likely to be clinically important. Our findings support the prescription of SSRI antidepressants in a wider group of participants than previously thought, including those with mild to moderate symptoms who do not meet diagnostic criteria for depression or generalised anxiety disorder. Full-Text PDF Open Access