A Review of the Efficacy and Adverse Effects of Fluoxetine in the Treatment of Generalized Anxiety Disorder

Background: Generalized anxiety disorder (GAD) is a persistent mental illness that causes significant distress and impairment in functioning. Selective serotonin reuptake inhibitors (SSRIs) are often used in the treatment of GAD, but evidence for fluoxetine in particular is not as well established as for some other pharmacological options.

Purpose: This review examined the efficacy and adverse effects of fluoxetine in the treatment of GAD while also considering treatment tolerability, pharmacokinetic variability, and emerging personalized medicine approaches.

Methods: A structured narrative review was conducted using PubMed/MEDLINE, PsycINFO, Embase, the Cochrane Library, and Scopus, with database searches conducted between January and April 30, 2026. Nineteen publications were included in the final synthesis, comprising direct adult GAD–fluoxetine studies, pediatric and mixed-anxiety fluoxetine studies, systematic reviews and network meta-analyses, and supportive safety, pharmacokinetic, pharmacogenetic, and biomarker research. Direct adult GAD evidence was distinguished from indirect or supportive evidence throughout the review.

Results: Several studies reported decreases in anxiety symptoms with fluoxetine, but direct adult GAD evidence was limited and did not establish superiority over other pharmacological treatments. However, systematic reviews and network meta-analyses yielded inconsistent results, and the evidence specific to fluoxetine was limited by small sample sizes, open-label designs, and limited data from placebo-controlled trials. Common adverse effects included nausea, insomnia, agitation, dry mouth, and sexual dysfunction. Differences in fluoxetine and norfluoxetine concentrations were associated with CYP2D6 genotype, but present evidence does not support routine genotype-guided dosing of fluoxetine. Biomarker- and patient-specific approaches remain preliminary and are not established for clinical decision-making in GAD.

Conclusions: Fluoxetine may be a treatment option for some patients with GAD, but current evidence does not establish superiority over SSRIs or serotonin-norepinephrine reuptake inhibitors (SNRIs) with stronger GAD-specific evidence. Larger, adequately powered, longer-term placebo-controlled trials are needed to clarify fluoxetine’s efficacy and tolerability in GAD and to evaluate the possible role of individualized treatment strategies.