Antidepressants – more is not necessarily better

Optimisation of antidepressant use has remained elusive despite an increased range of pharmacotherapy options. A recent systematic review and dose-response meta-analysis of double-blind, randomised controlled trials involving fixed doses of five selective serotonin reuptake inhibitors, in addition to venlafaxine, or mirtazapine for the acute treatment of adults with major depression has examined doses of SSRIs converted to fluoxetine equivalents. Trials of antidepressants for patients with depression and a serious concomitant physical illness were excluded. The main outcomes were efficacy, tolerability and acceptability, assessed after a median of 8 weeks of treatment. After applying filters there were a total of 77 studies were included, involving 19 364 participants; mean age 42·5 years, 11 749 reported were women). For SSRIs dose-efficacy curves showed a gradual increase up to doses between 20 mg and 40 mg fluoxetine equivalents, and a flat to decreasing trend through the higher licensed doses up to 80 mg fluoxetine equivalents. Dropouts due to adverse effects increased steeply through the examined range. The relationship between the dose and dropouts for any reason indicated optimal acceptability for the SSRIs in the lower licensed range between 20 mg and 40 mg fluoxetine equivalents. Venlafaxine had an initially increasing dose-efficacy relationship up to around 75–150 mg, followed by a more modest increase, and for mirtazapine efficacy increased up to a dose of about 30 mg and then decreased. Both venlafaxine and mirtazapine showed optimal acceptability in the lower range of their licensed dose. These results accord with what is widely observed in clinical practice – increasing the dose of antidepressants does not necessarily yield significant increases in efficacy, but may compromise tolerability. Relentlessly pushing the dose of an antidepressant does not necessarily increase the likelihood of success, and may in fact come at the cost of extra side effects and drug interactions.