There is little to choose between the different classes of antidepressant drugs in terms of efficacy; Selective Serotonin Re-uptake Inhibitors (SSRIs) are better tolerated and are safer in overdose than other classes of antidepressants and should be considered first-line for treating depression.

Discuss antidepressant treatment options with the person with depression, covering the choice of antidepressant (including side effects, discontinuation symptoms, and potential interactions with concomitant medication or physical health problems) and the person's perception of the efficacy and tolerability of any antidepressants they have previously taken.

Take into account toxicity in overdose when choosing an antidepressant for people at significant risk of suicide (see below). There may be an interval of 2 weeks before the antidepressant action takes place and during the first few weeks of treatment, there is an increased potential for agitation, anxiety, and suicidal ideation.

There is no evidence as yet supporting the use of specific antidepressants for patients with particular chronic physical health problems. For guidance on the use of antidepressants in patients with renal or hepatic impairment, epilepsy or cardiac conditions, refer to the Devon Partnership NHS Trust Prescribing Guidelines , the BNF and individual summary of product characteristics (SPCs).

Consideration may be given to short-term concomitant treatment with a benzodiazepine (section 4.1.2 Anxiolytics) if anxiety, agitation and/or insomnia are problematic symptoms during the early stages of treatment; this should usually be for no longer than 2 weeks in order to prevent the development of chemical addictive problems. Consideration should be given to the patient's risk of falls; avoid if chronic anxiety is present prior to commencing antidepressant or if patient has a previous history of chemical addictive problems. Alternatively, consider changing the antidepressant if problematic.

Initial antidepressant

See section 4.3 Antidepressant drugs for formulary antidepressants.

The first choice of antidepressant should be an SSRI because SSRIs are equally effective as other antidepressants and have a favourable risk–benefit ratio.

Considerations when prescribing SSRIs:

• SSRIs may exacerbate sleep disturbance and cause symptoms such as anxiety, restlessness and agitation. These symptoms can be self-limiting and individuals might benefit by persevering with treatment for an initial period to see if their experience improves.
• There is an increased risk of CNS toxicity when SSRIs are given with tramadol. Tramadol may also cause serotonin syndrome with other antidepressants. Refer to NICE CG91, summary of product characteristics (SPCs) and the BNF for specific details relating to individual drug interactions prior to prescribing any SSRI.
• SSRIs are associated with an increased risk of bleeding, especially in older people or in people taking other drugs that have the potential to damage the gastrointestinal mucosa or interfere with clotting (e.g. NSAIDs, aspirin, clopidogrel, oral steroids, warfarin, and heparins). Consider an alternative antidepressant or use a gastro-protective agent (e.g. proton pump inhibitor; section: 1.3 Antisecretory drugs and mucosal protectants)
• Hyponatraemia (usually in the elderly) has been associated with all types of antidepressants; however, it has been reported more frequently with SSRIs than with other antidepressants. Hyponatraemia should be considered in all patients who develop drowsiness, confusion, dizziness, convulsions, nausea, muscle cramps or seizures while taking an antidepressant. Stop the antidepressant if hyponatraemia occurs and consider an alternative when restarting if there are no confounding factors
• Sexual dysfunction is a common symptom of depression. However, in addition to this, all antidepressants can cause sexual dysfunction to varying degrees (most commonly serotonin reuptake inhibitors).
• SSRIs have been associated with a small increased risk of fractures. For further details, refer to MHRA guidance (2014)

Preferred first choice SSRIs:

Sertraline

• Adult over 18 years, initially 50mg daily, increased if necessary by increments of 50mg at intervals of at least 1 week to a maximum of 200mg daily; usual maintenance dose 50mg daily
• In patients with unstable angina or who have had a recent myocardial infarction, sertraline has been shown to be safe.
• Sertraline is considered to have a lower propensity for drug interactions in comparison to other SSRIs

Fluoxetine

• Adult over 18 years, 20mg daily increased after 3–4 weeks if necessary and at appropriate intervals thereafter; maximum 60mg daily (elderly usual maximum 40mg daily but 60mg can be used)
• Fluoxetine is generally associated with a higher propensity for drug interactions than other formulary SSRIs.
• Fluoxetine is a recognised treatment in the management of children and young people with depression. See guidance below for further details.

Alternative SSRIs:

Escitalopram

• Adult over 18 years, 10mg once daily, increased if necessary up to 20mg daily (Elderly over 65 years, initially 5mg once daily; maximum 10mg daily)

Citalopram

• Adult over 18 years, 20mg once daily increased if necessary in steps of 20mg daily at intervals of 3–4 weeks; maximum 40mg daily (Elderly over 65 years, initial dose 10-20mg, maximum 20mg daily)

Citalopram and escitalopram have been found to prolong the QT interval in a dose dependent manner and are contraindicated in people who are already taking medication known to prolong the QT interval, people with congenital long QT interval or those who have pre-existing QT interval prolongation; refer to 4.3.3 Selective serotonin re-uptake inhibitors and the MHRA drug safety update (2014). See also Drugs that prolong the QT interval, formulary guidance.

Switch to another formulary choice SSRI if the initial SSRI is not tolerated or is ineffective.

Treatment following failure of two 1st line antidepressants

See section 4.3 Antidepressant drugs for formulary antidepressants.

If the second SSRI is ineffective or unacceptable to the individual then prescribe a better tolerated newer-generation antidepressant.

Mirtazapine

• Adult over 18 years, initially 15–30mg daily at bedtime increased within 2–4 weeks according to response; maximum 45mg daily as a single dose at bedtime or in 2 divided doses
• Reversible blood dyscrasias, including agranulocytosis, have been reported infrequently in people taking mirtazapine. This usually occurs after 4–6 weeks of treatment and is reversible after stopping treatment
• Drowsiness often occurs during the first few weeks of treatment. This effect is not dose-related and should not prompt a reduction in dose (as this will lead to reduced efficacy). In most people this drowsiness is transient.

If treatment is ineffective and/or not tolerated consider an alternative antidepressant.

Alternative antidepressants

See section 4.3 Antidepressant drugs for formulary antidepressants.

These antidepressants are less well tolerated and should only be used in depression where there is a lack of response to the above agents or special individual circumstances dictate their use.

Take into account toxicity in overdose; compared with other equally effective antidepressants recommended for routine use in primary care, venlafaxine is associated with a greater risk of death from overdose. Tricyclic antidepressants (TCAs), except for lofepramine, are associated with the greatest risk in overdose

Lofepramine

• Adult over 18 years, 140–210mg daily in divided doses; elderly may respond to lower doses

Venlafaxine

• Adults over 18 years, initially 75 mg once daily, increased if necessary up to 375 mg once daily, dose to be increased if necessary at intervals of at least 2 weeks, faster dose titration may be necessary in some patients; maximum 375 mg per day.
• Modified release capsules should routinely be offered since they provide more consistent blood levels than immediate-release venlafaxine
• Compared with other equally effective antidepressants, venlafaxine is associated with a greater risk of death from overdose. Refer to MHRA Drug Safety Update 2014 for further details.
• Hypertension may occur in people taking venlafaxine, especially those taking high doses. Monitor patients for signs and symptoms of cardiac dysfunction and any increase in blood pressure

Trazodone

• Adult over 18 years, 150mg (elderly 100mg) daily in divided doses after food or as a single dose at bedtime; may be increased to 300mg daily; hospital patients up to maximum 600mg daily in divided doses

Vortioxetine

• Adult 18 – 64 years, 10mg once daily; adjusted according to response to 5–20 mg once daily
• Adult 65 years and over, initially 5 mg once daily; increased if necessary up to 20 mg once daily
• NICE TA367: Vortioxetine is recommended as an option for treating major depressive episodes in adults whose condition has responded inadequately to two antidepressants within the current episode (November 2015)

Where an individual has failed to respond to treatment with the regimens described above obtain specialist advice to consider augmentation/combination strategies.

Augmentation strategies/combinations

'Augmentation' describes the process when an antidepressant is used with a non-antidepressant drug and 'combination' describes when two antidepressants are used together.

In severe and psychotic episodes of depression, and when symptoms have not responded adequately to monotherapy, specialist mental health services may recommend using combination or augmentation strategies with commonly used formulary psychotropic medication.

These treatment regimens should only be started in primary care in consultation with a consultant psychiatrist or by a GP with specialist knowledge.

Prescribers should select medications that are known to be safe when used together and be aware of the increased side-effect burden this usually causes. Discuss the rationale with the person with depression, consider the licensing status of treatments prescribed and monitor carefully for adverse effects.

The following treatments should not routinely be used to augment antidepressant therapy: valproate, buspirone, carbamazepine, lamotrigine, pindolol, thyroid hormones or greater than two weeks' treatment with benzodiazepines.

Where an individual has failed to respond to treatment, obtain further specialist advice to consider alternative diagnosis and treatment.

A person with depression started on antidepressants who is considered to present an increased suicide risk, or is younger than 30 years (because of the potential increased prevalence of suicidal thoughts in the early stages of antidepressant treatment for this group), should normally be seen after 1 week and frequently thereafter (as appropriate) until the risk is no longer considered clinically important (see Suicide risk, below).

For people started on antidepressants who are not considered to be at increased risk of suicide, review after 2 weeks, and regularly thereafter, for example at intervals of 2 to 4 weeks in the first 3 months, and then at longer intervals if response is good.

If the person's depression shows no improvement after 2 to 4 weeks with the first antidepressant, check that the drug has been taken at the prescribed dose.

If response is absent or minimal after 3 to 4 weeks of treatment with a therapeutic dose of an antidepressant, increase the level of support and consider:

• Increasing the dose in line with the summary of product characteristics (SPC) if there are no significant side effects or
• Switching to another antidepressant if there are side effects or if the person prefers.

If the person's depression shows some improvement by 4 weeks, continue treatment for another 2 to 4 weeks. Consider switching to another antidepressant if:

• Response is still not adequate or
• There are side effects or
• The person prefers to change treatment

When reviewing antidepressants – it should be noted that elderly patients may take longer to respond.

Continuation and duration of treatment

Support and encourage a person who has benefited from taking an antidepressant to continue medication for at least 6 months after remission of an episode of depression (about 12 months in the elderly). The dose of antidepressant required to achieve remission should be continued. Review the need for continued antidepressant treatment beyond 6 months after remission, taking into account the number of previous episodes of depression, risk of relapse, the presence of residual symptoms, concurrent physical health problems and psychosocial difficulties, and the person's preference.

Advise people with depression to continue antidepressants for at least 2 years if they are at risk of relapse. When deciding whether to continue maintenance treatment beyond 2 years, re-evaluate with the person with depression, taking into account age, comorbid conditions and other risk factors.

Risk factors for relapse of major depression include:

• Presence of residual symptoms
• Number of previous episodes
• Previous history of recurrent depression
• Severity of most recent episode
• Duration of most recent episode
• Degree of treatment resistance in previous episode

Advise people with depression who are taking antidepressants that discontinuation symptoms may occur on stopping, missing doses or, occasionally, on reducing the dose of the drug. Explain that symptoms are usually mild and self-limiting over about 1 week, but can be severe, particularly if the drug is stopped abruptly. Discontinuation symptoms include increased mood change, restlessness, difficulty sleeping, unsteadiness, sweating, abdominal symptoms and altered sensations.

When stopping an antidepressant, gradually reduce the dose, normally over a 4-week period, to minimise the risk of discontinuation effects. Some people may require longer periods, particularly with drugs with a shorter half-life (such as venlafaxine, and paroxetine (non-formulary)). This is not generally required with fluoxetine because of its long half-life; however people taking higher doses (40 mg to 60 mg daily) may require gradual withdrawal. For individuals reporting discontinuation symptoms that are intolerable or distressing, consider reintroducing the original antidepressant at the dose that was effective (or another antidepressant with a longer half-life from the same class, e.g. fluoxetine for Selective Serotonin Re-uptake Inhibitors (SSRIs)), and reduce the dose gradually while monitoring symptoms.

When switching antidepressants, consideration should be given to whether cross-tapering is required or existing treatment withdrawn with a washout period before starting the next. General switching advice is to cross taper cautiously between the two antidepressants, bearing in mind the risk of serotonin syndrome (see below) when switching between two serotonergic agents. In some cases however, cross-tapering may not be necessary such as when the effects are so similar that administration of the second medicine is likely to ameliorate withdrawal effects of the first e.g. when switching from one SSRI to another. Abrupt cessation may also be acceptable when switching to a medicine with a similar, but not identical, mode of action. Consideration should be given to individual patient circumstances when determining whether cross-tapering is required.

In particular prescribers should note caution when switching:

• From a non-reversible MAOI: a 2-week washout period is required (other antidepressants should not be prescribed during this period)
• From fluoxetine to non-reversible MAOI – wait 5 weeks after stopping
• From fluoxetine (or paroxetine, non-formulary) to a tricyclic antidepressant (TCA); both of these drugs inhibit the metabolism of TCAs. A lower starting dose of the TCA will be required, particularly if switching from fluoxetine because of its long half-life (approximately 1 week). Recommend stopping fluoxetine for 4-7 days first

More detailed advice on switching antidepressants can be found in the Maudsley Prescribing Guidelines; local specialist advice and support can be obtained from Devon Partnership NHS Trust, details available here.

Serotonin syndrome

The term 'serotonin syndrome' is used to describe significant 'serotonin toxicity' and the two terms tend to be used interchangeably.

Serotonin syndrome or toxicity results in certain symptoms consisting of a triad of features: alteration of mental status, neuromuscular abnormalities and autonomic hyperactivity. These three features are not necessarily present together in every patient; symptoms include confusion, delirium, shivering, sweating, changes in blood pressure and myoclonus.

Serotonin syndrome can occur from overdose of a serotonergic agent, drug interactions, and taking one serotonergic agent alone in susceptible individuals. Drug interactions are particularly relevant when considering switching between antidepressants. The most severe cases are seen when monoamine oxidase inhibitors (MAOIs), are taken in combination with SSRIs, TCAs or venlafaxine. This is because the mechanism of action of MAOIs is to inhibit the breakdown of serotonin. Serotonin syndrome usually occurs within a few hours of drug or dose changes, resolving within about 24 hours of stopping the serotonergic drug(s).

The use of antidepressants has been linked with suicidal thoughts and behaviour; children, young adults, and patients with a history of suicidal behaviour are particularly at risk.

Where necessary patients should be monitored for suicidal behaviour, self-harm, or hostility, particularly at the beginning of treatment or if the dose is changed. Monitor patients for akathisia, suicidal ideas, and increased anxiety and agitation, particularly in the early stages of treatment with a Selective Serotonin Reuptake inhibitor (SSRI) (see below). Patients should be advised to seek help promptly if these are distressing.

Take into account toxicity in overdose when choosing an antidepressant for people at significant risk of suicide. Be aware that compared with other equally effective antidepressants recommended for routine use in primary care, venlafaxine is associated with a greater risk of death from overdose. Tricyclic antidepressants (TCAs), except for lofepramine, are associated with the greatest risk in overdose

A person with depression started on antidepressants who is considered to present an increased suicide risk or is younger than 30 years (because of the potential increased prevalence of suicidal thoughts in the early stages of antidepressant treatment for this group) should normally be seen after 1 week and frequently thereafter (as appropriate) until the risk is no longer considered clinically important.

In accordance with the National Suicide Prevention Strategy for England, people who have a history of self-harm in the last 3 months should receive no more than 14 days' supply of medication. This quantity should also be applied when prescribing a new treatment for someone thought to be at risk of suicide.

SSRIs and Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs)

The MHRA (2014) advised that there is a risk of suicidal behaviour with the use of any SSRI or SNRI, particularly when used by children, adolescents or young adults.

In 2008, a meta-analysis of data on antidepressants, including SSRIs and SNRIs, was completed by the Food and Drug Agency (FDA) in the USA. The results of this analysis were reviewed in both the UK and in Europe.

The UK/EU review concluded that the risk of suicidal acts and behaviour is increased with the use of SSRIs or SNRIs in young people aged up to 25 years. The risks of sertraline, citalopram, escitalopram, paroxetine, venlafaxine, and mirtazapine outweigh the benefits when used in children and adolescents with depression and should not be used in this patient group.

The risk of suicide is greatest in the early stages of SSRI treatment. This may be due to the fact that SSRIs and SNRIs need to be taken for a few weeks before they are effective in treating depression (which is itself associated with an increased risk of suicidal behaviour).

No psychotropic medication has a UK marketing authorisation specifically for women who are pregnant or breastfeeding.

During pregnancy a pragmatic discussion is required weighing the risks versus the benefits of treatment for both the individual and unborn child. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The woman (or those with authority to give consent on her behalf) should provide informed consent, which should be documented. In the postnatal period treatment options must take into account the individuals' preferences including consideration of treatment that allows for breastfeeding rather than recommending not to breastfeed.

The UK Teratology Information Service (UKTIS) provides a national service on all aspects of the toxicity of drugs and chemicals in pregnancy (Tel: 0344 892 0909), and provides the 'best use of medicines in pregnancy' (bumps) website for supportive information relating to individual treatments. UK Drugs in Lactation Advisory Service (UKDILAS) provides evidence based information on the use of drugs during the breastfeeding period to all UK healthcare professionals.

Clinicians must check with up to date sources of information before prescribing in this area. Refer to the following resources for further guidance:

• NICE clinical guideline 192: Antenatal and postnatal mental health: clinical management and service guidance
• Devon Partnership NHS Trust Prescribing Guideline: PG18 - Pharmacological Management of Perinatal Mental Health Conditions
• BNF and BNF-C
• Individual summary of product characteristics (SPCs)

Devon Partnership NHS Trust Perinatal Mental Health Teams may be contacted on the following numbers, for guidance relating to individual patients:

• Exeter: 01392 406532
• North Devon: 01271 322772
• Torbay: 01803 654605
• Self referral guidance to the Depression and Anxiety Service (DAS), is available here

Livewell Southwest Perinatal Mental health Team may be contacted via:

• livewell.perinatalmht@nhs.net
• 01752 431607
• Self referral guidance to Plymouth Options, is available here

The guidance that follows is based on NICE CG28: Depression in children and young people (updated 2017), which covers identifying and managing depression in children and young people aged between 5 and 18 years.

Refer individuals to specialist child and adolescent mental health services (CAMHS) (see referral guideline links below).

Antidepressants should only be prescribed following assessment and diagnosis by a child and adolescent psychiatrist.

• Antidepressant medication should not be used for the initial treatment of children and young people with mild depression.
• Do not offer antidepressant medication to a child or young person with moderate to severe depression except in combination with a concurrent psychological therapy.

Arrangements must be made for careful monitoring of adverse drug reactions, as well as for reviewing mental state and general progress. The precise frequency will need to be decided on an individual basis

The MHRA (2014) advised that there is a risk of suicidal behaviour with the use of any Selective Serotonin Re–uptake Inhibitor (SSRI) or Serotonin and Noradrenaline Re-uptake Inhibitor (SNRI), particularly when used by children, adolescents or young adults.

In 2008, a meta-analysis of data on antidepressants, including SSRIs and SNRIs, was completed by the Food and Drug Agency (FDA) in the USA. The results of this analysis were reviewed in both the UK and in Europe.

The UK/EU review concluded that the risk of suicidal acts and behaviour is increased with the use of SSRIs or SNRIs in young people aged up to 25 years. The risks of sertraline, citalopram, escitalopram, paroxetine, venlafaxine, and mirtazapine outweigh the benefits when used in children and adolescents with depression and should not be used in this patient group.

The risk of suicide is greatest in the early stages of SSRI treatment. This may be due to the fact that SSRIs and SNRIs need to be taken for a few weeks before they are effective in treating depression (which is itself associated with an increased risk of suicidal behaviour).

Fluoxetine is the preferred antidepressant for moderate and severe depression in children and young people. Fluoxetine is the only antidepressant where the benefits outweigh the risks. Fluoxetine is licensed for children aged 8 years and above; the starting dose should be 10mg daily, increased if necessary to 20mg daily after 1 week. Consider lower doses for children of lower body weight. There is little evidence regarding the effectiveness of doses of fluoxetine higher than 20mg daily, but higher doses may be considered in older children of higher body weight and/or when, in severe illness, an early clinical response is considered a priority.

Advice should be sought from a child and adolescent psychiatrist prior to commencing second line therapies.

When a child or young person responds to treatment, medication should be continued for at least 6 months after remission (defined as no symptoms and full functioning for at least 8 weeks); e.g. 6 months after this 8-week period.

Where antidepressant medication is to be discontinued, the drug should be phased out over a period of 6 to 12 weeks with the exact dose being titrated against the level of discontinuation/withdrawal symptoms. It is recommended that this is overseen by a specialist.

See section 4.3.3 Selective serotonin re-uptake inhibitors.

Patient focussed resources

• Devon Partnership NHS Trust provides a range of resources relating to a variety of mental health conditions, treatments and medications
• The Royal College of Psychiatrists - A range of information leaflets on depression in several languages
• Patient.info - information on depression, antidepressants and suicidal thoughts
• Mind – A mental health charity with a range of resources which may benefit patients
• HeadMeds - Provides young people with general information about medication used to treat mental health conditions. Managed by the charity YoungMinds. The college of Mental Health Pharmacy has been involved with the production of medicine information on this site.

Self-referral

• Patients in Plymouth can self-refer to Plymouth Options, an IAPT (Improving Access to Psychological Therapies) service for depression & anxiety. This service is provided by Livewell Southwest.
• Patients in Exeter, east and mid Devon, north Devon, south and west Devon and Torbay can self-refer to the Depression and Anxiety Service (DAS) provided by Devon Partnership NHS Trust

Clinical referral guidelines

• Depression & Anxiety Service - psychological therapies for common mental health problems, provided by Devon Partnership NHS Trust
• Plymouth Options - IAPT (Improving Access to Psychological Therapies) Service referral guideline (Livewell Southwest)
• AccEPT Clinic (Accessing Evidenced Based Psychological Therapies) - mindfulness based cognitive therapy: northern, eastern and western Devon
• Child and Adolescent Mental Health Services (CAMHS): South Hams and west Devon

References

• Devon Partnership NHS Trust Prescribing Guideline: PG03 - Pharmacological Treatment of Unipolar Depression (2018)
• Devon Partnership NHS Trust Prescribing Guideline: PG18 - Pharmacological Management of Perinatal Mental Health Conditions (2018)
• NICE clinical guideline 90: Depression in adults: recognition and management (updated 2018)
• NICE clinical guideline 91: Depression in adults with a chronic physical health problem: recognition and management (2009)
• NICE clinical guideline 28: Depression in children and young people: identification and management (updated 2017)
• NICE clinical guideline 192: Antenatal and postnatal mental health: clinical management and service guidance (updated 2018)
• MHRA Guidance: Selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs): use and safety (2014)