Incidence of early anxiety aggravation in trials of selective serotonin reuptake inhibitors in depression

Acta Psychiatr Scand. 2017 Oct;136(4):343-351. doi: 10.1111/acps.12784. Epub 2017 Aug 31.


Objective: Selective serotonin reuptake inhibitors (SSRIs) may aggravate anxiety and agitation during the first days of treatment but the frequency of such reactions remains unknown.

Method: We analysed patient-level data from placebo-controlled trials of sertraline, paroxetine or citalopram in depressed adults. Somatic anxiety, psychic anxiety and psychomotor agitation as assessed using the Hamilton Depression Rating Scale (HDRS) were analysed in all trials (n = 8262); anxiety-related adverse events were analysed in trials investigating paroxetine and citalopram (n = 5712).

Results: After one but not two weeks, patients on an SSRI were more likely than those on placebo to report enhanced somatic anxiety (adjusted risk 9.3% vs. 6.7%); likewise, mean rating of somatic anxiety was higher in the SSRI group. In contrast, patients receiving an SSRI were less likely to report aggravation of psychic anxiety (adjusted risk: 7.0% vs. 8.5%) with mean rating of psychic anxiety and agitation being lower in the SSRI group. The adverse event 'nervousness' was more common in patients given an SSRI (5.5% vs. 2.5%). Neither aggravation of HDRS-rated anxiety nor anxiety-related adverse events predicted poor antidepressant response.

Conclusion: Whereas an anxiety-reducing effect of SSRIs is notable already during the first week of treatment, these drugs may also elicit an early increase in anxiety in susceptible subjects that however does not predict a poor subsequent response to treatment.

Keywords: adverse events; antidepressants; anxiety; depression; mega-analysis; selective serotonin reuptake inhibitors.

Publication types

  • Meta-Analysis

MeSH terms

  • Adult
  • Akathisia, Drug-Induced / etiology
  • Anxiety / chemically induced*
  • Citalopram / adverse effects*
  • Clinical Trials as Topic / statistics & numerical data*
  • Depressive Disorder / drug therapy*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Outcome Assessment, Health Care / statistics & numerical data*
  • Paroxetine / adverse effects*
  • Psychomotor Agitation / etiology*
  • Selective Serotonin Reuptake Inhibitors / adverse effects*
  • Sertraline / adverse effects*


  • Serotonin Uptake Inhibitors
  • Citalopram
  • Paroxetine
  • Sertraline