1188340
research-article2023
CPHXXX10.1177/17151635231188340C P J / R P CC P J / R P C
PRACTICE TOOL Peer-reviewed
Practice Tool * Peer-Reviewed
Antidepressant discontinuation and the role
of the pharmacist
Chelsea Geen, BScH, MES, PharmD, RPh
Introduction are at risk of being misdiagnosed with a relapse or other psy-
Clinical practice guidelines currently offer minimal guid- chiatric condition if antidepressant withdrawal symptoms are
ance for managing antidepressant withdrawal symptoms in not recognized.6 Despite the potential challenges when discon-
patients who are tapering or discontinuing these medica- tinuing antidepressants, long-term use may expose patients
tions.1 Although many guidelines recommend antidepressants unnecessarily to known side effects and risks of treatment,
should be tapered gradually, out of 21 guidelines studied in a including gastrointestinal upset or bleeds, insomnia, somno-
recent systematic review, none suggested how doses should lence and weight gain.5 Other reasons why an antidepressant
be reduced, how to manage symptoms of antidepressant may be discontinued include subtherapeutic response, drug
withdrawal or how to differentiate withdrawal symptoms vs interactions, changes to drug insurance coverage, pregnancy
relapse.1 Approximately half of the patients attempting a dose or patient choice.1,4,7
reduction or discontinuation of their antidepressant have with-
drawal symptoms, which can be severe and ongoing for some Withdrawal symptoms
patients.1-3 In addition, due to the overlap between anxiety and Symptoms of antidepressant discontinuation may be described
depression symptoms and those of antidepressant discontinu- as antidepressant discontinuation syndrome (ADS), discon-
ation, it may be challenging to determine which is occurring.2 tinuation symptoms or withdrawal symptoms.2,4 However, the
Since pharmacists are a common point of contact for many latter is now widely recognized as the most appropriate term.2
patients, we have an opportunity to identify and help manage These withdrawal symptoms may occur after taking any anti-
antidepressant discontinuation issues in our patients. depressant for more than a few weeks, and the common occur-
rence of these symptoms makes discontinuing antidepressants
When to discontinue antidepressants difficult.2,4,5 Factors such as poor coping strategies, relapse
Although duration of treatment varies depending on the worries, social support needs and previously failed attempts at
clinical situation or remission maintenance period, generally discontinuation may also result in patient hesitancy or fear of
antidepressant treatment is recommended to cease after a cer- stopping an antidepressant.1,8
tain length of time.1,4 Canadian guidelines recommend that Withdrawal symptoms associated with stopping any type
clinicians discuss discontinuation with their patients after 6 of antidepressant typically begin within 2 to 4 days after the
to 9 months of clinical remission, but in some patients (such medication is stopped or reduced in dose, while the duration
as those with frequent, recurrent or severe episodes or other of withdrawal symptoms can vary from weeks to months or
comorbidities), treatment may be suggested for at least 2 years.5 even years.5,6,8,9 In some patients, withdrawal symptoms may
There can be significant withdrawal risks when discon- occur within hours, may be severe, may be delayed by weeks or
tinuing an antidepressant too quickly, including mania, hypo- may be of a longer duration.2,4-6,8 Previously, the National Insti-
mania, suicide and suicidal ideation; withdrawal symptoms tute for Health and Care Excellence (NICE) guidelines noted
of restlessness and panic may worsen suicidal ideation, and that withdrawal symptoms in patients discontinuing antide-
patients should be monitored closely.4 In addition, patients pressants “can be mild”8—a perspective that is likely outdated.
© The Author(s) 2023
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DOI:10.1177/17151635231188340
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Table 1 FINISH: The core symptoms after stopping antidepressants4-6,11
Definition Examples
F—Flu-like symptoms Fatigue, lethargy, aches, headache, sweatiness
I—Insomnia Vivid nightmares or dreams
N—Nausea May include vomiting
I—Imbalance Vertigo, light-headedness, dizziness
S—Sensory disturbance Paresthesias, such as “brain zaps”*; tingling, burning
H—Hyperarousal Agitation, anxiety, irritability, mania, aggression, jerkiness, mood disturbance
*Unpleasant, electric shock-like sensations that could be caused by adrenergic withdrawal.4
Table 2 The risk of antidepressant discontinuation syndrome for specific medications4,12-14
Class Lower risk Intermediate risk High risk
SSRIs Fluoxetine Citalopram* Fluvoxamine*
Escitalopram* Paroxetine
Sertraline
SNRIs Levomilnacipran Desvenlafaxine†
Milnacipran Duloxetine†
Venlafaxine
TCAs Doxepin Clomipramine Amitriptyline*,†
Trimipramine Desipramine* Imipramine†
Doxepin Nortriptyline*,†
MAOIs Isocarboxazid
Moclobemide
Phenelzine
Tranylcypromine
Other Bupropion XL Trazadone* Mirtazapine*
Vilazodone*
Vortioxetine
Different references cite some medications in different risk categories. Withdrawal may occur with any antidepressant, and withdrawal risk can
also be influenced by other patient-specific factors.
MAOIs, monoamine oxidase inhibitors; SNRIs, serotonin and norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors;
TCAs, tricyclic antidepressants.
*May also be considered lower risk.
†
May also be considered intermediate risk.
NICE recently updated their recommendations in a draft stan- to using an antidepressant long-term, which is different
dard to include gradual dose reduction in these patients in from addiction.12 Proven risk factors for withdrawal symp-
order to decrease the severity of withdrawal symptoms.10 toms include a higher dose or longer treatment duration.4,12
The pneumonic “FINISH” can be used to quickly remem- In addition, younger age and previously experiencing with-
ber common antidepressant withdrawal symptoms (Table 1).11 drawal symptoms after doses were missed, reduced or stopped
Withdrawal symptoms can also vary based on antidepressant may indicate a higher risk of discontinuation symptoms.4,12
class and specific medication.4 Medications with a higher receptor affinity and shorter
half-lives are more likely to elicit withdrawal symptoms.4,5,12
Risk factors for withdrawal symptoms Fluvoxamine and paroxetine have the shortest half-lives of
Symptoms of withdrawal from an antidepressant can occur the selective serotonin reuptake inhibitors (SSRIs) and thus
when the drug is abruptly stopped or the dose is significantly have the highest risk in this class, while fluoxetine has the
reduced.4,5 These withdrawal symptoms are due to physical lowest.4,6 See Table 2 for medication risk of ADS grouped
dependence, which may occur due to the brain’s adaptation by class.4
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Withdrawal or relapse? It is important to note that these features are not “rules.”
It is important to distinguish withdrawal symptoms from a Patients may experience different timelines, such as delayed
relapse of anxiety or depression, as misdiagnosis of relapse onset of withdrawal symptoms or longer duration of resolu-
(rather than withdrawal) can result in patients remaining on tion. If there is ongoing diagnostic uncertainty, then clinical
antidepressants longer than clinically necessary.3,6 Given the judgment, close attention to the patient story and seeking con-
overlap between withdrawal symptoms and symptoms of anxi- sultation with a specialist may be necessary.
ety or depression, the following features may help elucidate a
diagnosis: Patient management
There are no validated tapering schedules for antidepressants,
•• Timing of symptom onset: In general, relapse symptoms but generally slower is better.4 Antidepressants should be
take more than a few weeks to develop compared to with- tapered gradually, and if withdrawal symptoms become severe,
drawal symptoms, which can appear within days of stop- the medication should be restarted on a slower taper.4,6,8 To
ping an antidepressant or changing the dose. However, in reduce the chance of antidepressant withdrawal symptoms,
some cases, the onset of withdrawal symptoms may also tapers can be performed over weeks or months.4 Guideline
vary; for example, fluoxetine has a longer half-life, and tapering recommendations vary, some suggesting between
thus withdrawal symptoms may be delayed by weeks or 4 weeks and 6 months, while others have no duration or even
longer.2 mention of tapering.1 Due to the lack of clinical evidence for
•• Timing of symptom resolution: In general, if symptoms specific tapering regimens, it is difficult to develop evidence-
resolve quickly after restarting the last effective antidepres- based recommendations. Until randomized controlled clinical
sant dose, it is unlikely to be a relapse.2,6,15 There is limited trial data are collected, guidance for tapering may be found
evidence on the time frame for resolution, but one source from retrospective and nonrandomized tapering studies,
suggests symptoms resolving within 1 to 2 weeks are more expert opinion, dose reduction regimens based on pharmaco-
likely indicative of withdrawal than a relapse.15 logic theory and patient experience of withdrawal.1 Tapering is
•• Presence of physical symptoms: In general, coinciding generally considered after being on a medication for more than
psychological and physical symptoms are more likely to be a few weeks, and adjusting the dose every 2 to 4 weeks, switch-
due to antidepressant withdrawal than a relapse.2 The FIN- ing to a fluoxetine cross-taper or compounding liquid prepara-
ISH pneumonic may be helpful in identifying more com- tions when doses become small are possible strategies.2,4,8
mon withdrawal symptoms. More recently, initial data from nonrandomized trials have
•• New intensity of symptoms: In general, if a patient has implied that hyperbolic tapering may decrease the occurrence
symptoms they did not experience when initially diagnosed of withdrawal symptoms.1 SSRIs have shown a hyperbolic dose-
with anxiety or depression, or symptoms are more intense response relationship with serotonin transporters, with trans-
than previously experienced, these are more likely due to porter inhibition dropping sharply at doses below the minimum
antidepressant withdrawal than signs of a relapse.7 SSRI therapeutic dose.16 Thus, tapering in a linear fashion may
Table 3 Example of a possible tapering plan for citalopram17
Citalopram daily dose Tablet and liquid formulation dosing Notes
40 mg 2 × 20 mg tablets Reduce dose every 2 to 4 weeks.
This taper follows dose reductions
20 mg 1 × 20 mg tablet of 50% of the previous dose. Some
patients may need a slower taper.
10 mg 1 × 10 mg tablet
5 mg ½ × 10 mg tablet (or liquid formulation)
2.5 mg Liquid formulation
1.25 mg Liquid formulation
0.6 mg Liquid formulation
STOP MEDICATION
This is one example of a possible tapering plan for citalopram. An example to illustrate a strict hyperbolic taper would be if the goal is a 10%
decrease in occupied serotonin receptors with each dose decrease, a taper schedule for citalopram could be 20 mg, 9.1 mg, 5.4 mg, 3.4 mg, 2.3 mg,
1.5 mg, 0.8 mg and 0.37 mg.16
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Table 4 Example of a possible tapering plan for paroxetine17
Paroxetine daily dose Tablet and liquid formulation dosing Notes
40 mg 1 × 40 mg tablet Reduce dose every 2 to 4 weeks.
This taper follows dose reductions
36 mg 1 × 30 mg tablet + 3 mL of 2 mg/mL liquid formulation of 10% of the previous dose. Some
32.4 mg patients may need a slower taper.
1 × 30 mg tablet + 1.2 mL of 2 mg/mL liquid formulation
When a liquid formulation is being used
29.2 mg 1 × 20 mg tablet + 4.6 mL of 2 mg/mL liquid formulation for tapering, one may also consider
just using liquid for dosing (instead of
26.2 mg 1 × 20 mg tablet + 3.1 mL of 2 mg/mL liquid formulation tablet + liquid).
23.6 mg 1 × 20 mg tablet + 1.8 mL of 2 mg/mL liquid formulation
21.3 mg 1 × 20 mg tablet + 0.65 mL of 2 mg/mL liquid formulation
19.1 mg 1 × 10 mg tablet + 4.55 mL of 2 mg/mL liquid formulation
17.2 mg 1 × 10 mg tablet + 3.6 mL of 2 mg/mL liquid formulation
15.5 mg 1 × 10 mg tablet + 2.75 mL of 2 mg/mL liquid formulation
13.9 mg 1 × 10 mg tablet + 1.95 mL of 2 mg/mL liquid formulation
12.6 mg 1 × 10 mg tablet + 1.3 mL of 2 mg/mL liquid formulation
[30 more steps]
0.6 mg 0.3 mL of 2 mg/mL liquid formulation
STOP MEDICATION
Many factors should be considered when creating a patient-specific tapering plan, including patient tolerance of withdrawal symptoms. As well,
in this example, these doses may be difficult for patients to measure. In these cases, clinical judgment along with patient preference and expert
opinion may be helpful to create patient-centred tapering plans.
elicit progressively severe withdrawal symptoms, particularly Box 1 Tips for pharmacists
below therapeutic doses. For example, decreasing citalopram
• Realistic information about antidepressant therapy is
from 20 mg to 15 mg will reduce serotonin transporter inhibi-
desired by patients.8
tion by 3% (absolute decrease), whereas decreasing from 5 mg to • Educating patients who are starting antidepressants
0 mg will reduce this inhibition by 58%. In order to have a linear about potential symptoms that may occur when
decrease in pharmacological effect, instead of reducing the dose their medication is missed or stopped abruptly will
by set amounts, a hyperbolic reduction using a fixed interval of better prepare them for discontinuation in the future,
biologic effect has been suggested16 (see Table 3 footnote for an and provide reassurance that these symptoms are
example). However, a barrier to using this method is that com- reversible, are not life-threatening and will resolve.4,6,8
pounding or liquid formulations may be required. Although • Similarly, patients may be hesitant about discontinuing
further research is needed to develop conclusive antidepres- an antidepressant; explaining a tapering plan and
sant tapering plans, some examples of possible tapering symptoms to monitor for will help with patient
schedules have been provided in Table 3 and Table 4.17 Note expectations.5,7,8
that these are examples only; other patient factors may affect • Inform patients that if symptoms do become
the tapering plan, and some patients may need slower tapers. problematic, they can be managed by resuming the
When liquid formulations are unavailable, compounding may previous dose of the antidepressant and following a
be required. slower taper.4
Symptom management for antidepressant withdrawal is • The Royal College of Psychiatrists (UK) has an
absent in clinical practice guidelines.1,4 If withdrawal symp- information sheet that may be helpful to patients
toms are severe, this may be an indication to slow the taper attempting to discontinue their antidepressants
to a more tolerable rate for the patient.2 In the absence of (https://www.rcpsych.ac.uk/mental-health/treatments-
clinical evidence, clinical judgment may be used to suggest and-wellbeing/stopping-antidepressants).
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treatment for mild symptoms such as nausea, headaches and antidepressant maintenance treatment.18 Other nonpharma-
sleep, only if appropriate. It is also important to remember cologic options that may be considered to treat depression
that many antidepressants are cytochrome P450 inducers (depending on severity) without or with medication are dis-
or inhibitors, so re-evaluating concurrent medications for cussed in the NICE guidelines and include guided self-help;
drug-drug interactions is also important when discontinu- group CBT or behavioural activation; individual CBT or
ing an antidepressant.4 behavioural activation; individual problem-solving; group
Finally, it may be helpful to discuss with patients the role exercise, mindfulness or meditation; interpersonal psycho-
of nonpharmacologic management in the prevention of therapy and counselling.19,20
relapse or recurrence. Alternatives to antidepressant treat-
ment include cognitive behavioural therapy (CBT) and
mindfulness-based cognitive therapy (MBCT). In a system- Conclusion
atic review of managing antidepressant discontinuation, As pharmacists, we have a valuable role in both educating
these psychological interventions led to improved patient patients as they begin antidepressant medication and support-
outcomes. The combination of tapering with CBT compared ing them through discontinuation (see Box 1 for a summary
to tapering and clinical management alone significantly of tips). Knowing the core symptoms of antidepressant with-
reduced the risk of relapse or recurrence, while tapering drawal, risk factors for withdrawal symptoms and distinguish-
with MBCT resulted in high discontinuation rates without ing withdrawal from relapse can help patients comfortably and
an increase in rates of relapse or recurrence, compared to effectively taper off antidepressants. ■
Chelsea Geen is a fifth-generation community pharmacist and medical writer especially interested in dermatology, mental health and medication safety. Contact
[email protected].
Acknowledgments: Thank you to Olivia Geen, MD, FRCPC, geriatrician at McMaster University and Director of Knowledge Translation at Outro Health, Brandon
Goode, cofounder of Outro Health and Mark Horowitz, MBBS, PhD, neuroscientist and Clinical Research Fellow in psychiatry at the NHS in England and cofounder
of Outro Health, for providing expertise and resources pertaining to antidepressant deprescribing.
Funding: Funding was provided by Outro Health to support the drafting of this manuscript. Final content was at the sole discretion of the author.
Conflicts of Interest: Funding provided by Outro Health, as above.
ORCID iD: Chelsea Geen https://orcid.org/0000-0002-1379-6293
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