Withdrawal Symptoms after Serotonin-Noradrenaline Reuptake Inhibitor Discontinuation: Systematic Review

Abstract

Background: Serotonin-noradrenaline reuptake inhibitors (SNRI) are widely used in medical practice. Their discontinuation has been associated with a wide range of symptoms. The aim of this paper is to identify the occurrence, frequency, and features of withdrawal symptoms after SNRI discontinuation. Methods: PRISMA guidelines were followed to conduct a systematic review. Electronic databases included PubMed, the Cochrane Library, Web of Science, and MEDLINE from the inception of each database to June 2017. Titles, abstracts, and topics were searched using a combination of the following terms: “duloxetine” OR “venlafaxine” OR “desvenlafaxine” OR “milnacipran” OR “levomilnacipran” OR “SNRI” OR “second generation antidepressant” OR “serotonin norepinephrine reuptake inhibitor” AND “discontinuation” OR “withdrawal” OR “rebound.” Only published trials in the English language were included. Results: Sixty-one reports met the criteria for inclusion. There were 22 double-blind randomized controlled trials, 6 studies where patients were treated in an open fashion and then randomized to a double-blind controlled phase, 8 open trials, 1 prospective naturalistic study, 1 retrospective study, and 23 case reports. Withdrawal symptoms occurred after discontinuation of any type of SNRI. The prevalence of withdrawal symptoms varied across reports and appeared to be higher with venlafaxine. Symptoms typically ensued within a few days from discontinuation and lasted a few weeks, also with gradual tapering. Late onset and/or a longer persistence of disturbances occurred as well. Conclusions: Clinicians need to add SNRI to the list of drugs potentially inducing withdrawal symptoms upon discontinuation, together with other types of psychotropic drugs. The results of this study challenge the use of SNRI as first-line treatment for mood and anxiety disorders.

Effects of Treatment Discontinuation in Clinical Psychopharmacology

“…Similar reactions also have been observed following discontinuation of vari ous antidepressants [29] but are especially strongly associ­ated with serotonin reuptake inhibitors (SRIs) [16, 30] and some serotonin-norepinephrine reuptake inhibitors (SNRIs) [31]. Typically, in adults and juveniles, they arise after discontinuing treatment that has been ongoing for many weeks or months and appear to be more likely if relatively high doses of short half-life agents are removed or reduced suddenly or rapidly [4, 5, 7, 9, 30, 31]. Such withdrawal reactions appear to be especially likely with paroxetine and venlafaxine, probably less with most other SRIs or SNRIs other than venlafaxine [4, 5, 7, 9, 30, 31], and still less with older antidepressants [16].…”

“…Typically, in adults and juveniles, they arise after discontinuing treatment that has been ongoing for many weeks or months and appear to be more likely if relatively high doses of short half-life agents are removed or reduced suddenly or rapidly [4, 5, 7, 9, 30, 31]. Such withdrawal reactions appear to be especially likely with paroxetine and venlafaxine, probably less with most other SRIs or SNRIs other than venlafaxine [4, 5, 7, 9, 30, 31], and still less with older antidepressants [16]. Among SRIs, the risk is especially low with the very long-acting antidepressant-anxiolytic fluoxetine, which sometimes has been substituted for short-acting SRIs in efforts to manage withdrawal symptoms by slow removal of the more slowly cleared agent [4, 5, 7].…”

Iatrogenic Factors in Psychopathology

“…Withdrawal symptoms, which may follow discontinuation of psychotropic drugs, such as benzodiazepines [36], antipsychotic medications [4, 37], and antidepressant treatment [38-40], are also a form of behavioral toxicity. Discontinuation symptoms typically appear within 3 days of stopping antidepressant medication or initiating a medication taper.…”

“…Untreated symptoms may be mild and resolve spontaneously in 1–3 weeks; in other cases, they may persist for months or even years [38-40]. Persistent postwithdrawal disorder has been described with different classes of psychotropic substances (e.g., mood fluctuations and anxiety disorders with antidepressant drugs, tardive dyskinesia and supersensitivity psychosis with antipsychotic medication, protracted insomnia for alcohol and benzodiazepine withdrawal, and major depression for cocaine and amphetamine withdrawal) [4, 38-40]. Events related to withdrawal with psychotropic drugs may thus be limited to the period of drug administration and/or persist long after their discontinuation.…”

“…The explanatory power of pharmacokinetics is limited for these phenomena, even if we take zero-order kinetics into account (only a fixed amount of drug is eliminated in a given interval of time because enzymes for biotransformation and elimination are saturated). Tapering does not appear to affect the occurrence of withdrawal reactions with antidepressant drugs [39, 40] and persistent postwithdrawal disorders months after discontinuation may occur [41]. Further, dosage increase is unlikely to restore response after loss of clinical effect [42].…”