Effect of SSRI discontinuation on anxiety-like behaviours in mice

Abstract

Background: Abrupt cessation of therapy with a selective serotonin reuptake inhibitor (SSRI) is often associated with a discontinuation syndrome, typified by numerous disabling symptoms including elevated anxiety, which is of unknown cause. Aim: Here, the effect of SSRI discontinuation on anxiety-like behaviour was investigated in mice. Methods: Mice were treated repeatedly with paroxetine, citalopram or saline using a 3-arm experimental design comprising saline, continued SSRI and discontinued SSRI. Mice were assessed over 5 days after SSRI discontinuation using the elevated plus maze (EPM) and other anxiety tests. Results: In an exploratory experiment mice discontinued (2 days) from paroxetine (12 days) showed evidence of increased anxiety on the EPM, although this effect was observed in male and not female mice. Follow-up studies confirmed the EPM findings in male mice discontinued (2 days) from paroxetine (12 or 28 days) or citalopram (12 days) compared to saline controls. Continued treatment with paroxetine was also anxiogenic on the EPM but this was not the case for citalopram. Paroxetine exposure for more than a week was required to elicit evidence of a discontinuation response, which did not obviously strengthen with increased frequency or duration of dose. Finally, SSRI discontinuation effects were not resolvable from continued treatment in other anxiety tests applied between 3 and 5 days post-discontinuation. Conclusion: Overall, the current study provides evidence for a short-lasting increase in anxiety-like behaviour in mice following SSRI discontinuation, and offers a means for the investigation of the neurobiological mechanisms involved.