Correspondence www.thelancet.com/psychiatry Vol 6 October 2019 805 mirtazapine recruited from four regions (three in North America and one in Asia). Cytochrome P450 (CYP) enzymes constitute the major metabolizing enzyme system in humans, and cyto- chrome P450 1A2, 2D6, and A4 are the major antidepressant-metabolising enzymes. A recent worldwide genetic study revealed the large extent of the genetic variability and interethnic dif- ferences in cytochrome P450 between major populations (North, Central, and South Americans; Europeans; Asians; and Africans). 2 As a limitation, the antidepressant dose (especially citalopram) in this meta-analysis was optimal for patients in North America and Europe, but not for those in Asia, South America, Oceania, and Africa. Therefore, further randomised control trials of antidepressants in such regions and subsequent meta-analyses are needed to determine global optimal doses that considers differences between major populations. I declare no competing interests. Hirofumi Hirakawa hira-hiro@oita-u.ac.jp Department of Neuropsychiatry, Oita University Faculty of Medicine, Yufu-city, Oita 879-5593, Japan 1 Furukawa TA, Cipriani A, Cowen PJ, Leucht S, Egger M, Salanti G. Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis. Lancet Psychiatry 2019; 6: 601–09. 2 Zhou Y, Ingelman-Sundberg M, Lauschke VM. Worldwide distribution of cytochrome P450 alleles: a meta-analysis of population-scale sequencing projects. Clin Pharmacol Ther 2017; 102: 688–700. 1 Timmerby N, Andersen JH, Sondergaard S, Ostergaard SD, Bech P. A systematic review of the clinimetric properties of the 6-item Version of the Hamilton Depression Rating scale (HAM-D6). Psychother Psychosom 2017; 86: 141–49. 2 Bech P. Is the antidepressive effect of second-generation antidepressants a myth? Psychol Med 2010; 40: 181–86. 3 Østergaard SD. Do not blame the SSRIs: blame the Hamilton Depression Rating Scale. Acta Neuropsychiatr 2018; 30: 241–43. 4 Furukawa TA, Cipriani A, Cowen PJ, Leucht S, Egger M, Salanti G. Optimal dose of selective serotonin reuptake inhibitors, venlafaxine and mirtazapine in major depression: systematic review and dose-response meta-analysis. Lancet Psychiatry 2019; 6: 601–09. 5 Bech P. Applied psychometrics in clinical psychiatry: the pharmacopsychometric triangle. Acta Psychiatr Scand 2009; 120: 400–09. on the HDRS (via items 4–6 on sleep difficulties, item 11 on somatic anxiety, item 12 on gastrointestinal symptoms, item 14 on genital symptoms, and item 16 covering weight loss). 1–3 By contrast, common adverse effects of mirtazapine—namely, sedation and weight gain—are likely mistaken for improvement of depressive symptoms on the HDRS (via items 4–6 on sleep difficulties and item 16 covering weight loss). Thus, the full HDRS carries an inherent bias against SSRIs and SNRIs and a bias in favour of mirtazapine. These biases were demonstrated by Bech in his 2010 publication. 2 Bech showed that effect sizes of SSRIs and duloxetine (an SNRI) were lower on the multidimensional 17-item HDRS than on the unidimensional six-item melancholia subscale of the HDRS (HDRS-6), 1 which does not include the adverse-effect sensitive items of the HDRS mentioned here. The opposite was the case for mirtazapine (appendix). 2 In the assessment of dose–response relationships of antidepressant drugs, the pure antidepressant effect and the adverse effects should be assessed separately. 5 Because of their use of the full version of the HDRS as the preferred measure of response to antidepressants, Furukawa and colleagues have most likely, inadvertently, double counted the adverse effects. A re-analysis of the dose–response relationship of anti- depressant drugs using a unidimen- sional core measure of depression that is less likely to be biased by adverse effects (eg, the HDRS-6) therefore seems warranted. Such an analysis will provide more informative results on the dose–response balance of the inten- ded (antidepressant) and unintended (adverse) effects of antidepressant drugs. I declare no competing interests. Søren Dinesen Østergaard soeoes@rm.dk Department of Affective Disorders, Aarhus University Hospital – Psychiatry, 8200 Aarhus N, Denmark See Online for appendix See Online for appendix I read with interest the Article by Toshi A Furukawa and colleagues in The Lancet Psychiatry 1 in which they des- cribed the dose–response meta-analysis of fixed doses of antidepressants for major depression, and examined their efficacy, tolerability, and acceptability. I would like to highlight the recruitment regions of the studies included in this meta-analysis. In this meta-analysis, 77 studies from different recruitment regions were included and they mentioned only that 40 (52%) were done in North America, 13 (17%) in Europe, five (6%) in Asia, three (4%) in South America, six (8%) in unspecified regions, and that ten (13%) were cross- continental. I checked the locations of the studies that were classified as cross-continental and unspecified (appendix), and identified a total of 100 recruitment regions across all 77 studies (North America: 48 [48%], Europe: 24 [24%], Asia: 12 [12%], South America: seven [7%], Oceania: three [3%], Africa: one [1%], unspeci- fied: five [5%]). Therefore, half of the studies were designed to recruit participants from North America, and a quarter from Europe. I also investigated the recruit- ment region for each antidepressant (appendix). For example, 10 studies of citalopram recruited from ten regions (six in North America and four in Europe); and four studies of In The Lancet Psychiatry , Toshi Furukawa and colleagues 1 report their meta-analysis of randomised controlled trials examining fixed doses of second-generation antidepressants, with the primary goal of clarifying the optimal doses within the therapeutic ranges. The authors conclude that “the lower range of the licensed dose achieves the optimal balance between efficacy, tolerability, and acceptability in the acute treatment of major depression.”