Diagnosis and Management of Antidepressant Withdrawal – Understanding the Hyperbolic Curve and SSRI withdrawal

CLASSIFICATION OF WITHDRAWAL SYNDROMES

[Chouinard and Chouinard, 2015]

New symptoms: 

• The peak of onset: 36-96 hrs; last up to 6 weeks
• Reversible
• Symptoms: nausea, headaches, sleep disturbances, anxiety, decreased concentration, agitation, dysphoria, aggression, depression Specific serotonin-related new symptoms: flulike symptoms, dizziness, tachycardia, diarrhoea, electric shock sensations, confusion, myoclonus, premature ejaculation

Rebound:

• 36-96 hrs; last up to 6 weeks
• Reversible
• Return of original symptoms at greater intensity: anxiety; psychic anxiety, somatic anxiety, panic, agitation, insomnia, depression, dysphoria, obsessions, compulsions
            

Persistent post-withdrawal disorders: 

• Persistent, but remain reversible
• 24 hrs to 6 weeks; may last several months 
• Persistent, but remain reversible
• Return of original symptoms at a greater intensity and or with additional symptoms
• Appearance of new symptoms related to emerging new mental disorders                                                                         

Relapse                                                               

• 24hrs to 6 weeks
• partial or complete remission
• Same episode returns

Recurrence

• 6 months or more
• Remission – complete or partial
• New episode

WITHDRAWAL SYMPTOMS 

The withdrawal syndrome is a cluster of somatic and psychological symptoms that can be indexed according to the Discontinuation Emergent Signs and Symptoms (DESS) checklist.

This self-reported checklist covers 43 symptoms of which the following are some of the more commonly reported:  

• Somatic symptoms – Malaise, dizziness, light-headedness, vertigo, paresthesias, fatigue, headache, nausea, tremor, muscle spasms, diarrhoea, sweating, and hallucinations 

• Psychological symptoms – Anxiety, insomnia, emotional blunting, and irritability  

The FINISH acronym is also a useful guide in evaluation. [Berber, 1998]

• Flu-like
• Insomnia
• Nausea
• Imbalance
• Sensory disturbances
• Hyperarousal 

In addition, the abrupt cessation of TCAs may cause cholinergic-rebound phenomena (flu-like illness, myalgia and abdominal cramps).   

Antidepressants like mirtazapine which have antihistaminergic activity can cause an antihistaminergic rebound (insomnia, agitation, anxiety).

To minimise the effects of withdrawal, the APA and NICE recommend tapering doses over several weeks. [APA 2010];[ NICE 2010]

However, the extent of tapering depends on individual patient characteristics and the type of antidepressant and its duration and dose. [Fava et al, 2015];[Bosman et al, 2016]

NEUROBIOLOGY OF WITHDRAWAL

The neurobiological mechanisms of withdrawal are related to the receptor-rebound phenomenon whereby the sudden discontinuation of medication affects several feedback mechanisms that control serotonin neurotransmission. [Sharp et al. 2007]  

• During long term treatment, receptors are often downregulated or show reduced sensitivity to serotonin. 
• When SSRIs are abruptly removed, this causes a depletion of synaptic serotonin that is exacerbated by the hypoactive state of its receptors. 
• Antidepressant discontinuation causes symptoms that are features of major depression but can be differentiated from those of relapse or recurrence. 
• There are also downstream effects on other neurotransmitter systems such as dopamine and GABA, which are implicated in depression and the symptoms of other disorders. 

The risk of withdrawal symptoms is higher as the agent’s half-life shortens, particularly when they have been taken at a higher dosage over a longer period. Besides, there are class–specific effects based on receptor activity. For instance, tricyclic antidepressants have strong anticholinergic effects, and therefore withdrawal can be exacerbated by cholinergic–related symptoms (i.e. parkinsonism).

DIAGNOSTIC CRITERIA FOR SSRI AND SNRI NEW WITHDRAWAL

Criterion A:

• Duration of at least 6 months of continuous SSRI use prior to reduction or discontinuation 

Criterion B:

• ≥1 new symptom, common to CNS drugs, including nausea, headaches, tremor, sleep disturbances, decreased concentration, anxiety, irritability, agitation, aggression, depression, or dysphoria 

Criterion C:

• ≥2 specific new symptoms related to the serotonergic system, in particular, 5HT2A and 5HT1A receptors (see diagram above) 
• Characterised by a peak of onset within 36-96 h (depending on the drug duration of action) after cessation or reduction and by a symptom duration of up to 6 weeks (depending on drug elimination half-life).  

Criterion D:

• Symptoms cause clinically significant distress or impairment in important areas of functioning

Criterion E:

• Not due to a general medical condition, another mental disorder, or substance use. 

DIAGNOSTIC CRITERIA FOR SSRI AND SNRI REBOUND WITHDRAWAL

Criterion A:

• Duration of at least 6 months of continuous SSRI use prior to reduction or discontinuation 

Criterion B:

• Return of the illness’s original symptoms, such as anxiety, depression, or obsessions and compulsions. 
• It must be characterized by the presence of at least 4 of the following criteria:

1. Greater intensity of the symptoms than before treatment
2. Rapid appearance of the symptoms
3. Reversible
4. Transient
5. Psychological belief in the need for the drug
6. Rapid improvement of the symptoms after reintroduction of the drug. 

Criterion C:

• Symptoms in B are characterized by a peak of onset within 36-96 h (depending on the drug duration of action) after cessation or reduction and by a symptom duration of up to 6 weeks (depending on drug elimination half-life). 

Criterion D:

• Symptoms cause clinically significant distress or impairment in important areas of functioning,

Criterion E:

• Not due to a general medical condition, another mental disorder, or substance use. 

DIAGNOSTIC CRITERIA FOR SSRI AND SNRI PERSISTENT POSTWITHDRAWAL DISORDER

Criterion A:

• Duration of at least 6 months of continuous SSRI/SNRI use prior to reduction or discontinuation 

Criterion B:  

• The return of the original illness at a greater intensity than before treatment and/or the return of the original illness with additional symptoms (e.g.melancholic features for depression) or 
• The appearance of symptoms related to emerging new mental disorders
• ≥1 of the following: major depression, premenstrual dysphoria, generalized anxiety, panic attacks, insomnia, obsessive-compulsive and related illness, pathological gambling, posttraumatic stress, bulimia, bipolar spectrum illness, or symptoms of other DSM mental disorders. 

Criterion C:

Symptoms in B must persist longer than 6 weeks after drug discontinuation, and are characterized by two of the following criteria:  

1. Greater severity of illness than before treatment
2. Reversible with partial or total remission
3. Partial or total response to the reintroduction of the discontinued drug.  

Criterion D: 

• Characterised by a peak of onset within 24hrs to 6 weeks (depending on the drug duration of action) after cessation or reduction and by a symptom duration of up to 6 weeks (depending on drug elimination half-life) and may last several months or more 

Criterion E: 

• Symptoms cause clinically significant distress or impairment in important areas of functioning,  

Criterion F: 

• Not due to a general medical condition, another mental disorder, or substance use. 

MANAGEMENT OF SSRI OR SNRI WITHDRAWAL

Clinicians should aim to choose antidepressants with a favourable risk-benefit ratio in the treatment of depression.

Antidepressants vary in their propensity to cause withdrawal syndromes, and clinicians should consider this propensity in their choice of antidepressant for the patient.

1.Identify the different types of SSRI withdrawal. 

• Checklists, such as the DESS 

2. Gradual tapering: 

• Gradual tapering over a long period of time to discontinue an SSRI, for example, over several months if clinically appropriate. 
• By reducing the dose gradually, a plateau period develops that can help distinguish the development of new withdrawal symptoms, rebound, or recurrent symptoms (gradual withdrawal reduces new withdrawal and rebound symptoms but has no effect on persistent post-withdrawal disorders). 
• Use long half-life drugs such as fluoxetine. Long-acting drugs with a lower potential for withdrawal, abuse, or overdose, and a low incidence of side effects should be used. Importantly, if the patient is not already taking fluoxetine, it should be started during the SSRI tapering to aid in withdrawing from it. See tapering specifics later. 
• Paroxetine should not be given before exploring other treatment alternatives due to noradrenergic and cholinergic supersensitivity and shorter half-life.  

3.Evaluating Maintenance treatment: 

• Consider optimal maintenance dose by reducing medication gradually to find a minimal therapeutic dose. 
• Considering low doses of SSRIs and decreasing the lengths of SSRI maintenance treatment by using adjunct treatments, such as CBT, should be considered whenever possible to try to minimise long-term receptor changes. 
• Reevaluate overall treatment and management after 2 years of continuous SSRI use

According to the RANZCP 2020 guidelines : [Malhi et al., 2021]

It is generally recommended that patients should stop their antidepressant medication after they have been in remission for around 9 months to a year. Following ceasing medication, many patients will remain depression-free, but some may have a depressive relapse and up to 40% may experience discontinuation or withdrawal symptoms. 

4. Anticonvulsants: 

Anticonvulsants such as gabapentin and lamotrigine may be beneficial in SSRI withdrawal due to their antikindling effect. Lamotrigine may also be beneficial as an adjunctive therapy with SSRIs to treat depression as it has a depression-stabilising effect. [Chouinard and Chouinard, 2015] 

TAPERING PRINCIPLES

At present, most guidelines recommend that tapering is linear until the minimum effective dose for the relevant antidepressant is achieved.

For example, fluoxetine can be safely reduced over the course of just 2 weeks, whereas paroxetine requires a reduction of 5 mg every 2 to 4 weeks to prevent discontinuation symptoms. [Himei and Okamura 2006]

The main reason for this difference in tapering regimens is the difference in each drug’s half–life: antidepressants with shorter half-lives require longer periods of tapering than those antidepressants with longer half-lives. This is primarily because abrupt changes in available ligand can disrupt homeostasis. 

1. Paroxetine – dose range of 10 to 60 mg/day and a half-life of 21 hours 
2. Sertraline – dose range of 50 to 200 mg/day and a half-life of 26 hours 
3. Escitalopram – dose range of 10 to 30 mg/day and a half-life of 27 to 32 hours 
4. Citalopram – dose range of 10 to 60 mg/day and a half-life of 35 hours 
5. Fluoxetine – dose range of 20 to 80 mg/day and a half-life of 84 to 144 hours 

It is also important to note that for paroxetine, withdrawal symptoms can appear within 2 days compared to the 2 to 6 weeks it can take for fluoxetine withdrawal symptoms to appear. [Zajecka et al. 1998] ; [Fava et al. 2015] However, factors such as age, genetics, and the effect on specific CYP enzymes can dramatically change the pharmacokinetics of each drug. [Preskorn 1997] 

TAPERING REGIMENS

A PET study in 2004 by Meyer and colleagues showed that the binding potential of citalopram to SERT is proportional to receptor density and that the dose-response curve is hyperbolic. [Meyer et al. 2004]

A recent review nicely illustrated this point by showing the effect of a linear tapering regimen on the percentage inhibition of SERT [Horowitz and Taylor 2019]:  

1. SERT inhibition decreases by 3% when citalopram is reduced from 20 mg/day to 15 mg/day 
2. Then, when reducing citalopram from 15 mg/day to 10 mg/day and from 10 mg/day to 5 mg/day, SERT inhibition decreases by 6% and 13%, respectively. 
3. Finally, when reducing citalopram from 5 mg/day to 0 mg/day, there is a 58% reduction in SERT inhibition.

This means that SERT inhibition is dramatically reduced at lower doses and therefore, linear tapering is likely to cause withdrawal symptoms eventually.

Therefore, when tapering antidepressants, clinicians are suggested to follow a regimen that focuses on biological effect (e.g. SERT occupancy) rather than arbitrarily withdrawing medication using a linear stepwise approach.

We suggest that a personalised rate for withdrawal could be established by an initial trial reduction of SSRI dose, equivalent to a reduction of 10% serotonin transporter occupancy (or 5% if being cautious), with subsequent monitoring of the severity and duration of withdrawal symptoms.

An initial 10% reduc­tion in serotonin transporter occupancy is suggested because this would result in approximately halving the dose from the therapeutic minimum dose (eg, from 20 mg to 10 mg of citalopram), which is tolerated well by most patients.

If the patient’s Discontinuation ­Emergent Signs and Symptom score were to have returned to baseline 1 month after the initial reduction, then a rate equivalent to 10% reduction of serotonin transporter occupancy per month could be prescribed. This process should be subject to ongoing monitoring, with the rate titrated to patient tolerance. [Horowitz and Taylor 2019]

From a practical viewpoint, it may be necessary to switch to liquid formulations given the requirement for micro-modifications of dose during the later tapering stages.

According to the RANZCP Guidelines:[Malhi et al., 2021]

We suggest that, for those with risk factors for severe discontinuation and withdrawal symptoms (DaWS), the first step is to reduce the dose to the minimal effective dose. Following this, the dose should be halved, and after a week, the dose should be reduced more slowly in small decrements (allowing 2 weeks for each dose reduction), according to how the tablet can be divided. Unfortunately, this is not feasible with medications that are encapsulated (e.g. venlafaxine and duloxetine).  

When starting on an antidepressant, inform patients that they may experience discontinuation and withdrawal symptoms, and they should not stop antidepressants abruptly. They should discuss stopping their antidepressant with their treating physician. 

Recommendations from RANZCP Guidelines: 

Due to the substantial variability in individuals responses to the tapering of medication, the reduction should be individually tailored to the patient.

The dose of AD should be tapered down with the dose generally lowered in at least weekly steps, and the rate of stepping down the dose needs to be tailored to the individual patient.  

• Initially, titrate down to the recommended minimum effective dose of the antidepressant.  
• Once the minimum effective dose is achieved, reduce the dose by no more than 50% weekly. 

For patients with one or more risk factors for withdrawal and discontinuation symptoms (treatment at higher than usual dose, long-term period on an antidepressant, previous discontinuation and withdrawal symptoms or symptoms emerging with missed dose(s)), a slower taper is recommended. 

• Initially, drop to the recommended minimum effective dose of the antidepressant.
• Reduce the dose by small decrements (dependent on how the tablets can be cut up) every 2 weeks 

For patients stopping their medication to switch to another antidepressant because of lack of efficacy or intolerable side-effects, a more rapid dose reduction can be used (over days) while the new antidepressant is introduced at a low dose. The dose is then increased (provided there are no contraindications for this, such as switching to and from an MAOI). 

Discontinuation/withdrawal symptoms from the first antidepressant (after careful review of the symptoms the patient reports) need to be distinguished from treatment-emergent side-effects from the newly introduced antidepressant. 

However, some patients find that the above regimes may still result in substantial withdrawal symptoms despite the gradual reduction in whom a longer duration and /or more gradual reduction may be needed.

The RCPsych guidance on stopping antidepressants showed two examples of SSRI dose reductions; 50% every 2-4 weeks and 10 per cent every 2-4 weeks using tablets and liquid.

A recent large real-world observational study from the WHO pharmacovigilance database studied the risk of withdrawal syndrome comparing 15 antidepressants. [Quilichini et al, 2022]

Among the 338,498 reports with antidepressants of interest, there were 15,507 cases of withdrawal syndrome. According to the study;

Short half-lives antidepressants were associated with an increased risk of reporting a withdrawal syndrome compared to long half-life antidepressants (ROR 5.38; 95% CI 5.16-5.61). The risk was higher for 18-44 years old (ROR 6.88; 95% CI 6.17-7.62), women (ROR 1.38; 95% CI 1.33-1.43) and patients treated with Paroxetine, Desvenlafaxine, Venlafaxine and Duloxetine.

SUMMARY

Antidepressant withdrawal is associated with a cluster of distressing symptoms that are associated with medication half-life and homeostatic changes. In some cases, these withdrawal effects can be long-standing and protracted. 

However, the symptoms of withdrawal can be mitigated through the application of personalised tapering regimens that aim to minimise the incidence and severity of withdrawal symptoms.

Clinicians should take antidepressant withdrawal risk into account in addition to other side effects in choosing antidepressants for their patients.