Dose-response effects of selective serotonin reuptake inhibitor monotherapy for the treatment of depression: systematic review of reviews and meta-narrative synthesis

Abstract

Objective: To assess and clarify the relations between selective serotonin reuptake inhibitor (SSRI) dose efficacy, acceptability (early treatment discontinuation (dropouts)), and tolerability (reported adverse drug effects), and critically evaluate methods previously used to examine SSRI dose-response effects for the treatment of depression in adults.

Design: Systematic review of reviews and meta-narrative synthesis.

Data sources: Embase, Medline, PsycINFO, Scopus, and the Cochrane Collaboration library, from 1975 to December 2021. Reference lists of national depression treatment guidelines were systemically searched by hand.

Eligibility criteria for selecting studies: Reviews assessing SSRI monotherapy dose-response effects for the treatment of depression in adults (age ≥18 years) reporting efficacy, acceptability, or tolerability. Reviews meeting inclusion criteria had a high degree of heterogeneity, due to methodological diversity; therefore, a meta-narrative synthesis approach was applied. Standard daily doses were defined as 20 mg citalopram, fluoxetine, paroxetine; 50 mg sertraline; and 10 mg escitalopram. Risk of bias was assessed using the Risk of Bias in Systematic Reviews tool, in line with Cochrane recommendations.

Results: The search identified 9138 records; 387 full text reports were assessed for eligibility, 42 of which matched the inclusion criteria. The majority, 83% (n=35), of reviews included data for studies with a duration of ≤12 weeks (ie, the acute phase of depression treatment). Of 39 reviews assessing efficacy, the majority (n=26) indicated that individual SSRIs and SSRI class demonstrated flat dose-response effects; standard doses were optimal for efficacy. Acceptability or tolerability were assessed in 28 reviews. Higher than standard daily doses were associated with higher dropout rates and a greater incidence of adverse drug effects (eg, nausea, sexual dysfunction, fatigue, anxiety). Despite a range of methods being reported, there was an overall consensus regarding SSRI dose related efficacy, dropouts, and adverse drug effects.

Conclusion: Standard daily doses of SSRIs for the treatment of depression in adults provide a favourable balance between efficacy, acceptability, and tolerability. Patients are encouraged to talk to their prescriber or community pharmacist if they experience adverse effects or have any concerns about their drug treatments.

Keywords: Mood disorders; Pharmacology; Psychiatry.

Figure 1

Review identification, inclusion, and exclusion. *Total records identified include combined records from Embase, Medline, and PsychInfo (n=8728), plus those from Scopus and Cochrane. †Number of records listed are those identified from each database (rather than the total number across all databases). ‡No automated tools used, as per PRISMA 2020 guideline. SSRI=selective serotonin reuptake inhibitors; ADE=adverse drug effect

Figure 2

ROBIS (risk of bias in systematic reviews) assessment of all 42 reviews meeting inclusion criteria. First four columns relate to judgments; last column relates to overall rating for risk of bias

Figure 3

Corrected covered area pairwise matrix of primary studies citations. Pairwise analysis of review citations assessed as being at low risk of bias. Overlap categorisation: slight (0-5%; white), moderate (6-10%), high (11-15%; yellow), very high (>15%; red)