Discontinuing an antidepressant?
Tapering tips to ease distressing symptoms
- 2.2% with sertraline
- 14% with fluvoxamine
- 20% with paroxetine
- 30.8% with clomipramine.
These rates come from a retrospective case note review of patients who discontinued antidepressants under supervision.18 In a small cohort of outpatients being treated for major depressive disorder, stopping venlafaxine XR was associated with discontinuation symptoms for the next 3 days in 7 of 9 patients (78%), compared with 2 of 9 patients (22%) stopping placebo.11
Diagnostic criteria have been proposed for ADS associated with serotonin (5-HT) reuptake inhibitors.19-22 Proposed ADS definitions differ somewhat, but essentially 3 features guide the diagnosis:
- appearance of characteristic symptoms (Table 2)21,23
- timing of those symptoms, which usually emerge within 1 week of abrupt cessation or marked reduction of the antidepressant
- symptoms generally are mild, short-lived, self-limiting, and/or rapidly reversed by restarting the original antidepressant.
Evidence suggests shorter half-life antidepressants may be associated with the highest risk for ADS, but other risk factors remain presumptive (Table 3).
Table 1
FINISH: Symptoms of antidepressant discontinuation syndrome
| Flu-like symptoms |
| Insomnia |
| Nausea |
| Imbalance |
| Sensory disturbances |
| Hyperarousal (anxiety/agitation) |
| Source: Reference 1 |
Table 2
ADS symptoms can range across a variety of system clusters
| System cluster | Symptoms |
|---|---|
| Neurosensory | Vertigo, paresthesias, shock-like reactions, myalgias, numbness, sensitivity to sound, unusual visual sensations, ringing in the ears |
| Neuromotor | Tremor, myoclonus, ataxia/gait instability, visual changes, restless legs, problems with speech, tongue movements |
| Gastrointestinal | Nausea, vomiting, cramps/bloating, diarrhea, anorexia |
| Neuropsychiatric | Anxiety/panic, depression, mood swings, suicidal ideation, irritability, impulsivity, confusion, psychosis |
| Vasomotor | Diaphoresis, flushing, temperature intolerance |
| Other | Headache, insomnia, vivid dreams, nightmares, lethargy/fatigue, flu-like symptoms |
| ADS: antidepressant discontinuation syndrome | |
| Source: Construct suggested by Shelton,21 with additional symptoms added from other sources, including the discontinuation symptom checklist of Rosenbaum et al23 | |
Table 3
Possible patient risk factors for developing ADS*
| Abrupt antidepressant discontinuation |
| Shorter half-life antidepressants |
| Intermittent nonadherence/noncompliance |
| Interrupted treatment or use of ‘drug holiday’ |
| Specific antidepressant properties (such as potent [5-HT] receptor antagonism, cholinergic effects) |
| Younger patient age (including children and adolescents) |
| Female gender |
| Pregnancy |
| Neonate/breast-fed infant (mother on antidepressant therapy) |
| History of ADS |
| Vulnerability to depressive relapse |
| Duration of treatment (possible increased risk with more than 4 to 6 weeks of antidepressant exposure) |
| Switches to or between generic antidepressant formulations (related to variations in bioequivalence) |
| History of early adverse reactions when the antidepressant was initiated |
| ADS: antidepressant discontinuation syndrome |
| *Risk factors for ADS have not been rigorously studied in randomized controlled trials. Possible risk factors in this table were found in case reports |
What causes ADS?
Although the exact cause of ADS is unknown, the literature proposes several theories.
Because of the central serotonin system’s complex connections, acute reduction in synaptic serotonin when an SSRI or SNRI is abruptly or too quickly stopped may be the first in a cascade of steps affecting transmission of multiple monoamines. Parallels have been drawn between the phenomenon observed with rapid depletion of tryptophan—the essential amino acid precursor for the synthesis of 5-HT—and ADS seen with abrupt discontinuation of serotonergic antidepressants. This suggests that acute drops in neurotransmitter levels can precipitate neuropsychiatric and somatic manifestations of ADS.24
Patients’ uncomfortable symptoms likely are caused by the serotonin, norepinephrine, and cholinergic systems and their complex interactions.25 Individual genetic factors may influence patients’ vulnerability for ADS.
Managing ADS
Awareness and prevention. ADS can be misinterpreted as side effects of newly started treatment after an antidepressant is stopped. In Mr. J’s case, the appearance of muscle aches, headaches, and other ADS symptoms after ECT was started easily could have been perceived as adverse effects of ECT. Mr. J’s agitation and increased suicidal ideation could lead a clinician to mistakenly think that MDE was worsening because the antidepressant was stopped before ECT became effective. Being aware of ADS can prevent misdiagnosis and allow you to quickly identify the condition, manage the reversible syndrome, and continue with new treatment plan—in this case, ECT.
You can help prevent ADS by educating patients about the need to adhere to antidepressant regimens and to avoid missing doses. Consider ADS risk factors—particularly medications’ half-lives—before you start, change, or stop antidepressant therapy. Gradually taper all antidepressants being discontinued, with the possible exception of fluoxetine (which, including its active metabolite, has an elimination half-life of approximately 1 to 2 weeks).
Tapering antidepressants is more art than science because we have no controlled data to support any particular tapering regimen. Tailor the taper duration based on each patient’s response to sequential dosage reductions. Antidepressants with shorter half-lives—such as venlafaxine or paroxetine—may need to be tapered more slowly, perhaps by reducing the dosage by 25% every 4 to 6 weeks. If you plan to switch medications, this process may be expedited during a cross-taper to another antidepressant. You still may see discontinuation symptoms, however, depending on which new agent is chosen and which is being stopped.
