NPC Archive Item: No difference in effectiveness of ‘second-generation’ antidepressants

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A recent systematic review concludes that current evidence does not support the choice of one second-generation antidepressant (e.g. SSRIs, venlafaxine, duloxetine▼, mirtazapine) over another on the basis of efficacy or effectiveness.

Prescribers should continue to follow the NICE guideline for the management of depression. In view of the lack of evidence for a significant difference in efficacy between antidepressants, the choice should be based on their side-effect profile, patient preference, past experience with treatment, and cost.

Selective serotonin receptor inhibitors (SSRIs), are an appropriate first-line choice for most people where the prescribing of an antidepressant is appropriate (NICE recommends generic fluoxetine or generic citalopram).

What is the background to this?
NICE published its clinical guideline on the management of depression in 2004 (updated in 2007 to reflect MHRA advice regarding venlafaxine). The guideline provides recommendations for treatment options for depression of all severities, including the use of antidepressants. The NICE evidence-based review, reported in the Full Guideline, identified no clinically important difference between any of the antidepressants with regard to efficacy, including the tricyclic and second-generation antidepressants. A recent systematic review of clinical trial data of second-generation antidepressants was prepared to inform the American College of Physicians (ACP) in the development of their guideline for the use of second generation antidepressants. This review compared the benefits and harms of the SSRIs and other second-generation antidepressants licensed for use in the USA for depression.

What does this review claim?
Second generation antidepressants did not differ substantially in efficacy or effectiveness. There were very few statistically significant differences identified between individual agents, and where they were found, they were small and unlikely to have clinical significance. The evidence does not, therefore, warrant the choice of one second-generation antidepressant over another on the basis of efficacy. Although evidence was limited, no differences between individual antidepressants were found for patients with accompanying symptoms, or subgroups based on age, sex, race or ethnicity, or co-morbid conditions. Evidence was found for specific differences between antidepressants with regard to adverse effects and speed of onset of action, and these may be relevant for the choice of medication.

The subsequent ACP Guideline recommends that physicians choose second-generation antidepressants on the basis of their adverse event profile, cost and patient preference.

How does this relate to other studies?
This review confirms the results of previous systematic reviews comparing the efficacy of antidepressants, and is consistent with the NICE guideline recommendations.

So what?
In the absence of many large randomised controlled trials (RCTs) comparing individual antidepressants, the reviewers had to rely on meta-analyses of small studies and adjusted indirect comparisons to assess the differences between treatments. As a result they were not able to conclusively rule out differences in efficacy. However, in the limited number of cases where differences were found, the effect sizes were small and unlikely to be of clinical significance.

The review supports the NICE recommendations for choice of antidepressants in its clinical guideline for the management of depression. NICE recommends routine, careful monitoring of symptoms, side effects and suicide risk (particularly in those aged under 30), especially when initiating antidepressants. Patients who are prescribed antidepressants should be reviewed on a regular basis, beginning within one to two weeks after initiating treatment. If the drug has been taken regularly as prescribed, and there is no response to a standard dose of antidepressant, and there are no significant side effects, then an increase in dose can be considered. If there has not been a satisfactory response after a month (six weeks if there is a partial response), or the antidepressant is poorly tolerated, alternative treatment options should be considered. If it is decided to continue with antidepressant treatment, then a switch to a single alternative antidepressant can be considered. Reasonable choices for a second antidepressant include a different SSRI or mirtazapine, but consideration may also be given to other alternatives, including moclobemide, reboxetine and lofepramine.

See the NICE guideline for alternative options for the treatment of depression and more details of the factors to be considered when prescribing antidepressants.

Study details

Citation: Gartlehner G, et al.  Comparative benefits and harms of second-generation antidepressants: background paper for the American College of Physicians. Ann Intern Med 2008;10:734–50

Design: Systematic review and meta-analysis of head-to-head trials or adjusted indirect comparisons using meta-regression analysis and network meta-analysis.

Patients: Studies in adults only. The review included in the analyses six previous good- or fair-quality systematic reviews, 155 good- or fair-quality double-blind, placebo controlled, or head-to-head RCTs of at least six weeks duration. For harms, 35 observational studies with at least 100 participants and follow-up of at least 12 weeks were included.

Intervention: The antidepressants reviewed were: bupropion, citalopram, duloxetine▼, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone (not licensed in the UK), paroxetine, sertraline, trazodone, and venlafaxine.

Comparison: Relative benefit of response between individual antidepressants; descriptive review of studies with data on specific adverse effects and health-related quality of life.  Outcomes: Efficacy outcomes included the relative benefit (RB) of achieving response (more than 50% improvement from baseline), which reflects the weighted mean difference of changes on the Hamilton Depression Rating Scale or the Montgomery-Asberg Depression Rating Scale.

Efficacy — There were no statistically significant differences in efficacy between antidepressants with a very few exceptions, these were: citalopram vs. escitalopram (RB ratio 1.14, 95%CI 1.04 to 1.26 in favour of escitalopram); fluoxetine vs. sertraline (RB ratio 1.11, 95%CI 1.01 to 1.21 in favour of sertraine); fluoxetine vs. venlafaxine (RB ratio 1.21, 95%CI 1.01 to 1.24).

Onset of action — Seven fair-quality studies reported that mirtazapine had a significantly faster onset of action than citalopram, fluoxetine, paroxetine, or sertraline after one or two weeks of treatment. All studies were supported by the manufacturer of mirtazapine. However, after 4 weeks of treatment, most response rates were similar.

Adverse effects — Constipation, diarrhoea, dizziness, headache, insomnia, nausea, sexual adverse events, and somnolence were commonly and consistently reported. On average, 61% of patients in efficacy trials experienced at least one adverse event. Nausea and vomiting were the most common reasons for discontinuation in efficacy studies. Overall, second-generation antidepressants had similar adverse events profiles. The article contains a table summarising some differences in the incidence of specific adverse events.

Sponsorship: The study was supported by a grant from the Agency for Healthcare Research and Quality (USA).

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