Treatment of unipolar depression

For further details see Mental Health Prescribing Forum Prescribing Guideline PG03- Pharmacological Treatment of Unipolar Depression

Once depression has been diagnosed and a decision made to treat then the choice of treatment should be dictated by:

  • Duration of the episode of depression and the trajectory of symptoms
  • Previous episodes of depression and response to treatment
  • Likelihood of adherence to treatment and any potential adverse effects/interactions with existing medicines/chronic medical conditions
  • Individual treatment preference and priorities

Duration of treatment should be dictated by:

  • Severity of symptoms
  • Previous duration of episodes of depression and response to treatment
  • Treatment should be continued for at least 4 weeks (6 weeks in the elderly) before considering whether to switch antidepressant due to lack of efficacy. In cases of partial response, continue for a further 2 weeks (elderly patients may take longer to respond)
  • The individual's treatment preferences and priorities

Psychological therapies and social interventions are vital to the successful treatment of depression but are beyond the scope of this guideline.

Consider using a short course (maximum 2 weeks) of a benzodiazepine if an individual develops side effects such as acute anxiety, insomnia or agitation upon commencing an antidepressant. Bear in mind the patient's risk of falls and avoid if chronic anxiety is present prior to commencing antidepressant or if they have a previous history of chemical addictive problems.

Always ask individuals about adverse effects and aim to find an acceptable resolution for them. Tricyclic antidepressants (tricyclics) are less well tolerated than SSRIs, more toxic in overdose and should be avoided in people with a high risk of suicide. Lofepramine is considered safer in overdose than other tricyclics. Dosulepin should not be newly initiated and where appropriate its use should be reviewed.

Bleeding: in particular GI bleeding can occur with SSRIs and care must be taken when people are already taking medicines also associated with GI bleeding (e.g. NSAIDs, aspirin, clopidogrel, oral steroids, warfarin, and heparins). Consider an alternative antidepressant or use a gastro-protective agent.

Drug choices

When starting someone on an antidepressant they should be reviewed 2-4 weeks after starting treatment and regularly thereafter depending on their response to treatment. See below for advice on initiating treatment in patients with increased suicide risk.

Initial antidepressant

See 4.3 Antidepressant drugs

The first choice of antidepressant should be a selective serotonin re-uptake inhibitor (SSRI). Switch to another first choice SSRI if the initial SSRI is not tolerated or is ineffective.

SSRIs may exacerbate sleep disturbance and cause symptoms such as anxiety, restlessness and agitation initially. If sedation is required or in agitated depression, or panic disorder consider prescribing a benzodiazepine concurrently for the first 1–2 weeks (maximum 4 weeks). Alternatively, consider changing the antidepressant for a sedating antidepressant.

There is an increased risk of CNS toxicity when SSRIs are given with tramadol. Tramadol may also cause serotonin syndrome with other antidepressants.

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)

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); child 8–18 years, 10mg daily increased after 1–2 weeks if necessary, maximum 20mg daily
  • If there is no response to fluoxetine at lower doses, increasing the dose is unlikely to produce any additional benefit but side effects would be expected to increase.

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

Treatment following failure of two 1st line antidepressants

See 4.3 Antidepressant drugs

If the 2nd SSRI is ineffective or unacceptable to the individual then prescribe a better tolerated newer antidepressant.

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)

See 4.3 Antidepressant drugs for MHRA warning on citalopram

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

Alternative antidepressants

See 4.3 Antidepressant drugs

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 a special individual circumstance.

Venlafaxine

  • Adult over 18 years, initially 75mg daily in 2 divided doses increased if necessary at intervals of at least 2 weeks; maximum 375mg daily

Lofepramine

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

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

Best supported augmentation strategies/combinations

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

Antidepressant plus lithium (Priadel®)

SSRI/venlafaxine plus mirtazapine

Valproate and carbamazepine should not routinely be used to augment antidepressants in depression.

See Bipolar Disorder section for guidance on Lithium Monitoring.

Where an individual has failed to respond to treatment with the regimens described above consider obtaining specialist advice about diagnosis and treatment.

Antidepressants in special groups

For augmentation strategies please seek specialist advice.

Perinatal

Generally manufacturers recommend avoiding antidepressants in pregnancy and breastfeeding. However, a pragmatic decision is often required weighing the risks versus the benefits of treatment for both the individual and unborn child. For up to date advice contact the National Teratology Service (Tel: 0844 892 0909).

Renal impairment

  • Citalopram – dose reduction in severe renal failure may be prudent
  • Sertraline – no dosage adjustment is necessary in patients with renal insufficiency
  • Fluoxetine – maximum dose 40mg
  • Mirtazapine – care with higher doses recommended
  • Venlafaxine – dose halved in haemodialysis, in severe renal impairment and for patients on haemodialysis
  • Tricyclics – start low and go slow; lofepramine contra-indicated in severe renal impairment
  • MAOIs – no dose adjustments required

Hepatic impairment

  • Citalopram – maximum dose 20mg daily
  • Sertraline – contra-indicated in severe hepatic impairment. Use with caution in mild and moderate impairment
  • Fluoxetine – lower dose e.g. alternate day dosing recommended
  • Mirtazapine – dosage reduction may be necessary
  • Venlafaxine – dosage reduction may be necessary
  • Tricyclics – use lower starting doses and increase cautiously
  • MAOIs – moclobemide only, use lower doses

Children and adolescents

NICE CG28 Depression in children and young people

  • Refer individuals to specialist CAMHS services. Only prescribe following assessment and diagnosis by a child and adolescent psychiatrist.
  • Pharmacological treatment must only occur alongside psychological treatment.
  • Fluoxetine is considered suitable and is licensed.
    • 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.
  • Citalopram and sertraline are second-line options under defined circumstances and are not licensed in this age group
    • The starting dose should be half the daily starting dose for adults, increased if necessary to the daily adult dose gradually over 2 to 4 weeks. Consider lower doses in children of lower body weight.
    • There is little evidence regarding the effectiveness of upper daily adult doses in children and young people, but these may be considered in older children of higher body weight and/or when, in severe illness, an early clinical response is considered a priority.
  • Consider lower doses in low weight children
  • Do not use venlafaxine, tricyclics or paroxetine
  • In refractory depression consider augmenting with an antipsychotic if psychotic symptoms are present

Parkinson's disease

  • SSRIs should be considered 1st line for depression in Parkinson's Disease and that although some patients may experience a worsening of motor symptoms the absolute risk is low.

Older Adults

  • Avoid tricyclics and be wary of any chronic medical conditions that may affect choice of antidepressant. Older adults take longer to respond to antidepressant therapy and are more prone to side effects. Sertraline and citalopram are associated with fewer interactions but refer to appendix 1 of the BNF for more information on interactions
  • Avoid tricyclic antidepressants in dementia or where significant cognitive impairment is present.
  • Lithium can cause signs of toxicity within commonly accepted therapeutic ranges. Consider using lower ranges under specialist advice. See later for Lithium guidance
  • Hyponatraemia can occur with any antidepressant but is thought to be more common with SSRIs, especially in older women. Stop the antidepressant if hyponatraemia occurs and consider an alternative when restarting if there are no confounding factors

Cardiac conditions

  • Avoid tricyclics, especially dosulepin
  • Sertraline has been shown to be safe in people post-MI
  • Citalopram is associated with dose-dependent QT interval prolongation (see MHRA advice for further information). Mirtazapine is a suitable alternative to SSRIs in cardiac disease
  • Care must be taken when prescribing medicines with warfarin to be aware of any drug interactions. See section on bleeding above
  • Myocardial infarction - Avoid tricyclic antidepressants if previous MI. Sertraline may be used but try to avoid any antidepressant therapy for first two months post MI if possible.

Epilepsy

  • Citalopram does not interact with anticonvulsants so is considered low risk. Other SSRIs are considered to be low risk too but be wary of possible interactions. Venlafaxine and mirtazapine should be used with caution. Tricyclics are considered to be higher risk

Suicide risk

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.

There is an increased risk of suicide with antidepressants on starting therapy. Monitor patients for akathisia, suicidal ideas, and increased anxiety and agitation, particularly in the early stages of treatment with an SSRI. Patients should be advised to seek help promptly if these are distressing.

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.

Stopping and switching between antidepressants

When stopping an antidepressant gradually reduce the dose, normally over a 4-week period. This is to minimise the risk of discontinuation effects. Some people may require longer periods, particularly with drugs with a shorter half-life (such as paroxetine and venlafaxine). This is not required with fluoxetine because of its long half-life. In individuals experiencing troublesome discontinuation effects one option is to swap them to fluoxetine and stop this instead.

General switching advice is to cross taper cautiously between the two antidepressants, bearing in mind the risk of serotonin syndrome when switching between two serotonergic agents.

Exercise particular caution when switching:

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

More detailed advice on switching antidepressants can be found in the Maudsley Prescribing Guidelines. A quick-reference guide is available on the MIMS website

Long term use of antidepressants

Longer term use of antidepressants should be considered where there are several risk factors for relapse of depression. Evidence suggests that people with risk factors should continue antidepressant therapy for at least 24 months.

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

Patient focussed resources

 

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