Abrupt Discontinuation Compared With a 1-Week Taper Regimen in Depressed Outpatients Treated for 24 Weeks With Desvenlafaxine 50 mg/d

Abstract

The objective of this study was to determine whether the occurrence of discontinuation symptoms was equivalent for abrupt discontinuation versus 1-week taper to desvenlafaxine 25 mg/d after a 24-week treatment with desvenlafaxine 50 mg/d (administered as desvenlafaxine succinate) for major depressive disorder. Adult outpatients with major depressive disorder who completed the 24 weeks of open-label treatment with desvenlafaxine 50 mg/d were randomly assigned to no discontinuation (desvenlafaxine 50 mg/d), taper (desvenlafaxine 25 mg/d), or abrupt discontinuation (placebo) groups for the double-blind (DB) taper phase. The primary end point was Discontinuation-Emergent Signs and Symptoms (DESS) scale total score during the first 2 weeks of the DB phase. The null hypothesis that the absolute difference of greater than 2.5 in DESS scores between taper and abrupt discontinuation groups was tested by calculating the 95% 2-sided confidence interval on the mean difference between the 2 groups. Of the 480 patients enrolled in the open-label phase, 357 (≥1 postrandomization DESS record) were included in the primary analysis. Adjusted mean ± SE DESS scores were 4.1 ± 0.72 for no discontinuation (n = 72), 4.8 ± 0.54 for taper (n = 139), and 5.3 ± 0.52 for abrupt discontinuation (n = 146) groups. The difference in adjusted mean DESS total scores between the abrupt discontinuation and taper groups was 0.50 (95% confidence interval, -0.88 to 1.89) within the prespecified margin (±2.5) for equivalence. The number of patients who discontinued because of adverse events or discontinuation symptoms during the DB period was similar between the taper (2.8%) and abrupt discontinuation (2.1%) groups. These findings indicate that an abrupt discontinuation of desvenlafaxine 50 mg/d produces statistically equivalent DESS scores compared with the 1-week taper using 25 mg/d.

Effects of Treatment Discontinuation in Clinical Psychopharmacology

“…However, studies aiming to test the prediction that slow removal of drugs can reduce risk of withdrawal reactions are rare and most have major design limitations. For SRIs, these sometimes include lack of adequate controls, small numbers of subjects, multiple drugs with major pharmacokinetic differences, and short discontinuation times with few downward steps in dose, or lack of matching of the presence and severity of DESS outcome items at baseline [15, 40-42]. Despite such limitations, some findings suggest that gradual reduction of doses of SRIs may not provide important reduction of withdrawal symptoms.…”

“…A fourth study found little difference in risks of DESS- defined withdrawal symptoms after discontinuing various SRIs or venlafaxine given for depression over 3 versus 14 days, and that drugs of long half-life (mainly fluoxetine) and those of short half-life had similar risks of DESS-based withdrawal symptoms; however, depressive symptoms were more likely with rapidly eliminated agents, with associated new suicidal preoccupations and behaviors [32]. Finally, a trial involving desvenlafaxine given for depression and discontinued abruptly, over 2 weeks gradually, or not at all found that the risk of DESS withdrawal symptoms did not differ between those who continued the SRI or underwent rapid dose-lowering, although there was a highly significantly lower risk with gradual versus abrupt discontinuation [15]. In short, evidence concerning the value of slow discontinuation of drugs including modern antidepressants to minimize or avoid withdrawal reactions is limited, inconsistent, and often based on less-than-optimal study designs.…”

“…In a survey based on nine reports of such reactions, among 632 patients treated with an SRI, withdrawal-emergent reactions were identified in an average of 33.2% (95% CI: 31.3–35.1), indicating a substantial but minority prevalence [14]. Such reactions typically emerge within hours or a few days after major reductions of dose or complete removal of the suspect agent and can persist for widely different times from days or a few weeks, and less often, to many weeks [4, 7, 9, 15, 16]. A reassuring finding is that evidence of withdrawal symptoms in neonates born to mothers taking SRIs was not found in one study [35].…”

“…In addition to physical and sensory phenomena, reactions sometimes include symptoms also found in the illnesses being treated (especially depression and anxiety), as well as other novel syndromes. Examples of the latter include: withdrawal-emergent dyskinesias [9] or catatonia [10], emergence or worsening of tardive dyskinesia [11, 12], and a proposed tardive psychosis syndrome [13] – all on removal of antipsychotic drugs; new panic symptoms and worsening or new depression or mania after removing an antidepressant [3, 8, 14-16]; and new or increased suicidal behavior after discontinuing lithium [17] and possibly antidepressants [15, 16]. Second and usually somewhat later, symptoms of illnesses being treated can recur more often, sometimes more severely, and much more rapidly than predicted by the natural history of untreated illness, including by comparison to a patient’s own history.…”

Discontinuing Antidepressant Drugs: Lesson from a Failed Trial and Extensive Clinical Experience

“…Controlled studies indicate no significant advantages of slow tapering compared to abrupt discontinuation as to onset of withdrawal symptoms [2,3,17,[39][40][41]. Nonetheless, slow tapering with frequent contacts appears to be a reasonable strategy for many patients.…”