To the Editor: We thank Dr. Jindal for his thought-provoking remarks and agree that, in addition to weight gain, other pharmacological mechanisms, such as the M₃ muscarinic receptor affinity, might influence the risk of diabetes associated with certain antidepressants. However, one should note that a rather immediate receptor-mediated effect on the blood glucose homeostasis is not in accordance with the finding of an increased risk of diabetes only after >24 months of therapy. In addition, paroxetine not only has a higher M₃ receptor affinity than the other SSRIs under study but also differs in other important aspects. For example, it is the most potent inhibitor of serotonin re-uptake among the currently available SSRIs (2) and it is associated with a significantly higher weight gain than fluoxetine or sertraline (1). Since the tricyclic antidepressant dothiepin, which has a higher M₃ affinity than paroxetine (3), was not associated with an increased risk of diabetes in our study, the impact of M₃ receptor affinity remains unclear.

We agree with Dr. Jindal that drugs classified according to their most important pharmacological method of action can vary quite substantially in the frequency of certain side effects. In the discussion section of our article, we emphasized that individual SSRIs might differ with respect to their diabetogenic potential. However, there was no statistically significant difference in the risk of diabetes between paroxetine and fluvoxamine on the one hand and citalopram, fluoxetine, and sertraline on the other. Thus, highlighting differences within the class of SSRIs as one major finding of our study does not seem reasonable to us.

1.Fava M, Judge R, Hoog SL, Nilsson ME, Koke SC: Fluoxetine versus sertraline and paroxetine in major depressive disorder: changes in weight with long-term treatment. J Clin Psychiatry 2000; 61:863—8672.Marks DM, Park MH, Ham BJ, Han C, Patkar AA, Masand PS, Pae CU: Paroxetine: safety and tolerability issues. Expert Opin Drug Saf 2008; 7:783—7943.Stanton T, Bolden-Watson C, Cusack B, Richelson E: Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Biochem Pharmacol 1993; 45:2352—2354

References