Why does milnacipran produce so few discontinuation syndromes following abrupt withdrawal?

Several selective serotonin reuptake inhibitors (SSRI), especially paroxetine, have been reported to produce a number of post-treatment emergent adverse events following abrupt withdrawal (Coupland et al 1996; Haddad 1997). More recently a SSRI-induced neonatal withdrawal syndrome has been described (Sanz et al 2005) in infants born of mothers treated with SSRI during pregnancy. In both of these situations, paroxetine has been associated with the greatest incidence (Warner et al 2006; Sanz et al 2005). Other SSRIs and the selective serotonin and noradrenaline reuptake inhibitor (SNRI) venlafaxine can, however also cause a withdrawal syndrome in patients (Trenque et al 2002). In contrast, milnacipran, another SNRI, has been reported to present a lower risk of withdrawal-induced adverse events (Vandel et al 2004). Furthermore the spectrum of the symptoms was different from that produced by paroxetine. In our clinic, a discontinuation syndrome is sometimes seen when SSRIs or SNRIs are discontinued suddenly, or when doses are missed or forgotten. In a total cohort of 2675 depressed patients, we identifi ed 124 cases of antidepressant withdrawal syndrome. Sixty-three of the cases resulted from withdrawal from fl uvoxamine (from a total of 1306 treated patients), 55 were withdrawn from paroxetine (from a total of 453 treated patients), while 6 were withdrawn from milnacipran (from a total of 916 treated patients). With paroxetine and fl uvoxamine, respectively, the incidence of discontinuation syndrome was 18.4 times greater and 7.3 times greater than that found with milnacipran (Table1). These differences were highly signifi cant as determined by the χ 2 test. These results are qualitatively similar to those obtained in a double-blind comparative study of milnacipran and paroxetine by Vandel et al (2004), who found an incidence of discontinuation syndrome of 13% with milnacipran and 32% with paroxetine following withdrawal after 6 weeks of treatment. Paroxetine has systematically been found to have the highest incidence of discon-tinuation syndrome (Warner et al 2006) while fl uvoxamine has an incidence 10-fold lower and fl uoxetine 100-fold lower (Westenberg and Sandner 2006). Paroxetine is the most potent inhibitor of the serotonin transporter (Sanchez and Hyttel 1999) and this potency may be a signifi cant factor in the frequency of discontinuation syndromes for paroxetine in comparison with fl uvoxamine (Westenberg and Sandner 2006) and milnacipran (Moret et al 1985). Furthermore, paroxetine is unique among the SSRI because its relatively high affi nity for muscarinic receptors is similar to that of imip-ramine (Schatzberg …