Recent studies have confirmed the protective effects of lifestyle interventions against relapse of depression and suggest they might protect against depression.^1-3 This shift is accompanied by a clearer understanding of withdrawal symptoms while stopping an antidepressant.^4-6 This evidence assists GPs to frame the use of antidepressants along a pathway towards recovery, with the intention that the antidepressant will be withdrawn.

1. Start with lifestyle and non-drug therapies

Clinical guidelines aim for symptom remission, functional recovery, and long-term resilience.^7,12-15 Antidepressants are not recommended as first-line treatment for mild to moderate depression.¹⁶ Their benefits compared to placebo increase with increasing severity of depression.¹⁶

Most people with mild to moderate depression recover from their episode within a year with appropriate psychological care, support, and lifestyle intervention early in their illness.^15,20

Lifestyle therapies are underused across all types of depression.²¹ Long-term outcomes are improved when antidepressant medication is used in conjunction with non-pharmacological therapies.^22-24 This includes lifestyle interventions for sleep, exercise, mindfulness, time in nature, diet, smoking and social connections.^22-25 It also includes assisting people to change their social and family circumstances through access to services or other means.

Lifestyle interventions have protective benefits

The benefits of lifestyle interventions for depression are established.²⁶ For example, exercise is just as effective as medicines when treating mild to moderate depression.²⁶

A recent longitudinal study of seven lifestyle factors for reducing the risk of depression found that, even in people with polygenetic risk for depression:¹

• healthy sleep (7-9 hours) was most protective for a single depressive episode
• frequent social connection and never smoking were protective for a single depressive episode, treatment resistant depression, and recurrent depressive disorder.

Another twelve-year longitudinal study of people with depression found the risk of recurrent depression and mortality was reduced by similar lifestyle factors, as well as spending time in nature and regular employment.³

Both studies demonstrate that when lifestyle factors are combined together they have ever-increasing protective effects. People with a ‘favourable lifestyle’ had a 50–57% lower risk of depression and recurrence compared with people who had an ‘unfavourable lifestyle’.^1,3

This evidence suggests that incremental changes of modifiable lifestyle has tangible long-term benefits, moving people towards recovery and resilience. [See patient information brochure]

Assisting people in lifestyle and social change can involve a multidisciplinary team, including physiotherapists, psychologists, dieticians, sleep assessors, pharmacists and GP pharmacists. Practice nurses can also assist in connecting patients with resources that are cost appropriate, accessible and accommodate social and family responsibilities. Social prescribing is evolving with resources becoming increasingly available.

This one-page tool – ‘My lifestyle plan’ – can be used to help guide social prescribing of lifestyle interventions to aid your patient’s recovery.

2. Before starting an antidepressant

Where possible before starting an antidepressant, discuss the limited effectiveness and risks of the continued use of medication.²⁷ A management plan that involves starting antidepressants should include a strategy for regular review and, where feasible, address considerations for their eventual cessation.²⁷

Update on the risks of antidepressant use 

There are well-documented side-effects with the use of antidepressants which can have significant impact on people’s lives. These include sleep disturbance, weight gain and sexual dysfunction. Side-effects described as emotional numbness, fogginess and a reduction in positive feelings can occur, especially in people on medications for greater than 3 years.²⁷

Recently, long-term use has also been associated with surgery complications.²⁸ A 10-year follow up longitudinal study found association between antidepressant use (SSRIs and Mirtazapine) and cardiovascular mortality, coronary heart disease and all-cause mortality.²⁸ Long-term antidepressant use has been linked with an increased likelihood and severity of withdrawal syndrome.^4,29

Creating treatment plans for depression

Involve your patient in creating a treatment plan tailored for them and their circumstances.³⁰ This process should outline:

• the severity of a patient’s depression, and the possible social determinants

• treatment options and goals so that decisions can be mutually agreed upon

• initiation of psychological support and other non-pharmacological treatment options for optimal outcomes

• possible cause of depression

• whether an antidepressant will be initiated and its relative benefits
• how it might help
• what to expect when taking
• possible adverse effects, including likelihood of withdrawal syndrome
• when to report adverse effects emphasising that all reports of adverse events experienced are taken seriously
• how long before the antidepressant might start to have an effect and the approximate length of time it will need to be taken for

• a schedule of regular reviews of symptoms of depression and adverse effects.

3. Understanding antidepressant withdrawal

Antidepressant withdrawal (sometimes called ‘discontinuation symptoms, or withdrawal syndrome) is a result of dependence: the body adapts to maintain homeostatic equilibrium of neurotransmitters within the synapse in response to antidepressant effects.^5,27 With long-term use of antidepressants there is a reduction, or down-regulation, of post-synaptic serotonin receptors, as illustrated in Figure 2.

When antidepressant use is abruptly interrupted, ceased or reduced, the antidepressant is eliminated faster than the body is able to adapt through homeostasis. This mismatch between the physiological levels of serotonin and the down-regulated serotonin receptors result in withdrawal symptoms.⁴

Withdrawal symptoms are highly variable and have been reported across ten organ systems. The most common are:³¹

• General symptoms: headache, dizziness, insomnia, impaired concentration, fatigue, tremor, tachycardia, nightmares.
• Affective symptoms: depressed mood, irritability, anxiety, panic attacks.
• Sensory symptoms: ‘electric-shock’ sensations in the head (often on moving eyes), or in limbs, ataxia leading to falls, disorientation that impairs walking and driving.
• Gastrointestinal symptoms: nausea, vomiting, diarrhoea.
• Increase in suicide attempts in the 2 weeks after stopping an antidepressant.²⁷
• Akathisia – this is most recognised as a side effect of long-term antipsychotic use but can occur in withdrawal from antidepressants. Symptoms include pacing, and a sense of terror often described as, ‘feeling like the nervous system is on fire.’

Withdrawal is more prevalent and severe than first reported

A systematic review measuring incidence, duration and severity of antidepressant withdrawal found just over half of patients (56%) experience withdrawal symptoms.^4,6,32 For some people, withdrawal symptoms are mild and short‐lasting. However, survey data has found nearly half of people (46%) reported their symptoms as severe,³² which resulted in recommencing antidepressant use.⁴

Withdrawal symptoms are not always ‘self-limiting’, as many guidelines suggest.³² A study of self-reported patient experience found symptoms lasted between 6 weeks (from 40 to 80%) and more than 3 years (around 15%) depending on the types of antidepressants and the length of time they’ve been taken for.⁴

Withdrawal can be confused with relapse

It can be difficult to distinguish between withdrawal and relapse due to the overlap of symptoms. One study suggests between 31 to 54% of people who met the criteria for withdrawal also reached the threshold for detection of relapse (8 to 10 point increase in Hamilton Rating Scale for Depression scores).⁵ The misdiagnosis of withdrawal as relapse has called into question a Randomised Controlled Trial (RCT)³³ that claims continued use of an antidepressant protects against relapse.^5,27

When will a patient experience withdrawal?

Experience of antidepressant withdrawal varies between individuals depending on their neurophysiology and the nature of their antidepressant regime. The following five factors can help to predict the incidence and severity of withdrawal.

1. Antidepressant type

Withdrawal symptoms can occur within all classes of antidepressants, however likelihood and severity has been found to vary depending on antidepressant type.^4,34,35

2. Duration of use

There are no RCTs examining the severity of withdrawal and the duration of use. However, emerging evidence suggests the longer patients take antidepressants the more likely they are to experience withdrawal symptoms and for those symptoms to be severe and longer lasting.^4,6,27 About half of people who have been using antidepressants for more than 3 years will experience withdrawal effects that are moderate to severe. Many severe cases are recorded in people using antidepressants for over 3 years.⁴ A more recent review found that withdrawal effects were rarer (1 in 6, severe effects were 1 in 30).³⁴ Risk of withdrawal incidence and severity could be viewed as a sliding scale from short-term to longer-term use.⁴

3. Individual experience

A strong clinical indicator of the likelihood of withdrawal is if people have experienced withdrawal when they have ceased or reduced their medication for any reason.⁴ 

4. Dosage

Dosage appears to have a relationship with withdrawal, where higher doses increase the risk of incidence.⁴ However, dosage may not influence withdrawal as much as duration of use.

5. Stopping abruptly

Abrupt cessation of antidepressants is thought to disturb homeostasis rapidly, resulting in a large mismatch that leads to a greater chance of withdrawal symptoms (see tapering below).

4. Managing withdrawal for successful discontinuation of an antidepressant

There is limited evidence for the long-term protective effects of antidepressant medication, or its use as maintenance therapy beyond 3 years.⁷ The Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines recommend review of the progress of a patient’s depressive symptoms and side-effects of their medications every six months to assess the benefits and risks of continued use.⁷ They also recommend considering stopping antidepressants after a patient has been in remission for 9 to 12 months.⁷

Stopping the use of antidepressants might be an important step in a person’s recovery. Evidence suggests that 30–50% of people who have taken antidepressants for over two years have no evidence-based clinical indications for continuing.³⁶

People who could stop their antidepressant might be discovered in a patient review, or less often the discussion might be initiated by the person themself (7%).²⁷ Reasons for people wanting to stop may include resolution of symptoms, adverse effects outweigh the benefits, or pregnancy.

A comprehensive discussion about the risks of stopping the medication is recommended. Time constraints in the clinical interaction, conflicting priorities and fear of relapse are commonly reported barriers; whilst knowledge and skills about how to discontinue antidepressants were the main enablers to ceasing antidepressant use.^27,37

A person may require support to stop, with more regular GP appointments, while ensuring lifestyle, social and psychological factors are in place to help protect against relapse.²⁷ It might take time for a person to feel they have the appropriate coping skills and support.

How to distinguish relapse from withdrawal

Distinguishing relapse from withdrawal is important as they can be treated differently. Table 3 outlines the clinical characteristics of withdrawal and ways to differentiate it from relapse.

Withdrawal symptoms for fluoxetine, the SSRI with the longest half-life, have been observed to occur with a delayed onset of 4-6 weeks.

Hyperbolic tapering of an antidepressant reduces withdrawal

Antidepressant dose reduction or cessation should be individualised to the patient. Effective tapering helps protect against the frequency and severity of withdrawal symptoms. In studies where tapering was conducted over a longer period (up to 6 months) there was no increased chance of relapse compared with continuing antidepressants.³⁸

Some guidelines recommend short tapers of between 2 weeks and 4 weeks down to therapeutic minimum doses, or half-minimum doses, before complete cessation. However, evidence suggests that these tapers show minimal benefits over abrupt discontinuation and are often not tolerated by patients.³⁹

There is a higher success rate of stopping an antidepressant by tapering over months compared to tapering that occurs more quickly over weeks. This approach appears to reduce the risk of withdrawal symptoms.²⁷ Since the dose-response curves for SSRIs, SNRIs, and TCAs are hyperbolic,^6,26 a successful antidepressant tapering plan may benefit from utilising a hyperbolic dose reduction regimen.^6,27 This method of tapering minimises the mismatch at the receptor and decreases the incidence and severity of withdrawal symptoms because even a small amount of the medication can still have a large effect.²⁷

Pharmacists who specialise in mental health or compounding can help if considering hyperbolic tapering. They can assist with dose calculations and provide formulation advice as the antidepressant may need to be compounded into liquid formulation to achieve the required dosing. Compounding antidepressants into liquid formulations can be expensive which presents access issues for some patients. Examples of tapering plans for a variety of antidepressant medicines can be found here

Monitor for symptoms

Closely monitor people for symptoms while they’re tapering their antidepressant. Review tapering plan if a person experiences withdrawal symptoms:²⁷

No symptoms or only mild symptoms: continue with the tapering regimen and keep monitoring

Moderate to severe symptoms:  allow more time before further reductions to see if the symptoms resolve

Severe symptoms: - return to the last dose at which the person was stable and allow time to adjust and taper more slowly.

If the person is experiencing a relapse rather than withdrawal, return their medication to the previous therapeutic dose and review again in six months.²⁷