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Bosker 2010 Biochemical and behavioral effects of long-term citalopram administration and discontinuation in rats: role of serotonin synthesis.


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Possible neurochemical basis for antidepressant withdrawal syndrome. Also see Harvey 2003 Neurobiology of antidepressant withdrawal


Neurochem Int. 2010 Dec;57(8):948-57. Epub 2010 Oct 12.

Biochemical and behavioral effects of long-term citalopram administration and discontinuation in rats: role of serotonin synthesis.

Bosker FJ, Tanke MA, Jongsma ME, Cremers TI, Jagtman E, Pietersen CY, van der Hart MG, Gladkevich AV, Kema IP, Westerink BH, Korf J, den Boer JA.




University Centre of Psychiatry, University Medical Centre Groningen, University of Groningen, The Netherlands. f.j.bosker@psy.umcg.nl


Abstract at http://www.ncbi.nlm.nih.gov/pubmed/20946930 Full text PDF here.


We have investigated effects of continuous SSRI administration and abrupt discontinuation on biochemical and behavioral indices of rat brain serotonin function, and attempted to identify underlying mechanisms. Biochemistry of serotonin was assessed with brain tissue assays and microdialysis; behavior was assessed as the acoustic startle reflex. Long-term SSRI administration to rats reduced the content of 5-HT and its main metabolite shortly after inhibition of 5-HT synthesis in many brain areas with more than 50%. Turnover was not appreciably decreased, but significantly increased within 48h of drug discontinuation. The microdialysis experiments indicate that neuronal release of 5-HT depends strongly on new synthesis and emphasize the role of 5-HT(1B) receptors in the regulation of these processes. Discontinuation of the SSRI rapidly increased behavioral reactivity to the external stimulus. Additional startle experiments suggest that the increased reactivity is more likely related to the reduced extracellular 5-HT levels than to impaired synthesis. The combination of the marked reduction of serotonin content and limited synthesis may destabilize brain serotonin transmission during long-term SSRI treatment. These combined effects may compromise the efficacy of an SSRI therapy and facilitate behavioral changes following non-compliance.


From the paper:



Abrupt termination and non-compliance with SSRI medication occur more often than generally thought. Non-compliance may exceed 30% and the resulting discontinuation symptoms may not be recognized, which will negatively influence current and future treatment compliance (Demyttenaere and Haddad, 2000; Demyttenaere et al., 2001; Eaddy et al., 2005). Apart from the risk of rebound depression, abrupt termination of SSRI treatment results in about one third of the patients in a phenomenon referred to as the antidepressant discontinuation syndrome. Key features of SSRI discontinuation include aggression, irritability, agitation, anxiety and low mood (Warner et al., 2006). Discontinuation symptoms are generally reported within 1–7 days after termination or dose-decrease of the treatment (Warner et al., 2006). The symptoms are typically short-lived, and in principal not life-threatening, but in some patients discontinuation symptoms cause considerable morbidity. Although it is good clinical practice to slowly taper the SSRI, which reduces the frequency and severity of discontinuation symptoms considerably (Haddad, 2001; Sher, 2002; Schatzberg et al., 2006), this is unlikely to be the case with non-compliance.


Discontinuation symptoms have been connected with impaired serotonin function (Blier and Tremblay, 2006).


This is not medical advice. Discuss any decisions about your medical care with a knowledgeable medical practitioner.

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