This content was published in 2009. We do not recommend that you take any clinical decisions based on this information without first ensuring you have checked the latest guidance.
Identify knowledge gaps
- How soon after starting an antidepressant can a response be expected?
- What factors should be considered when switching antidepressants?
- If a patient collecting an antidepressant asked: “How long do I need to take this for?”, how would you answer?
Before reading on, think about how this article may help you to do your job better.
The Royal Pharmaceutical Society’s areas of competence for pharmacists are listed in “Plan and record”.
This article relates to “common disease states” (see appendix 4 of “Plan and record”).
Depression is a common and recurrent illness accounting for significant morbidity worldwide. Untreated depression increases the risk of death from suicides, accidents, heart disease, respiratory disorders and strokes. In addition, patients with diabetes, epilepsy or ischaemic heart disease have poorer long-term outcomes if they suffer from depression.
The effective treatment and management of depression is a challenge for all healthcare professionals. Pharmacists, in particular, have an important role to play to ensure the safe and effective use of antidepressants.
The terms “depressive episode”, “major depressive disorder”, “unipolar depression” and “clinical depression” have all been used to define the collection of symptoms that make up the severe and enduring illness of depression.
The term “depressive episode” is currently used by the World Health Organization in its “International classification of diseases”, currently in its 10th edition (ICD-10). In this, depression is classified as mild, moderate, severe or recurrent (see Panel 1).
Panel 1: Symptoms of depression and classification
- Lowering of mood
- Reduction of energy and decreased activity
- Loss of interest and enjoyment
- Reduced concentration
- Disturbed sleep
- Disturbed appetite
- Reduced self-esteem and self-confidence
- Ideas of guilt or worthlessness
- Marked psychomotor retardation
A mild depressive episode involves having two to three of the above symptoms. Although the patient will be depressed he or she will generally be able to continue with ordinary activities.
A moderate depressive episode involves four or more of the above symptoms and the patient is unlikely to be able to carry on with daily activities.
A severe depressive episode also involves four or more symptoms but these are distressing, typically including loss of self-esteem and ideas of worthlessness or guilt. Suicidal thoughts and acts are also common.
A recurrent depressive disorder is characterised by repeated episodes of depression without any history of independent episodes of mood elevation and increased energy.
Other forms of depression, such as depression with psychotic symptoms or atypical depression, are recognised but will not be discussed in this article.
The lowered mood can vary from day to day, is unresponsive to circumstances and is typically present for at least two weeks. Two simple screening questions that may help identify those suffering from depression are:
- During the past month, have you often been bothered by feeling down, depressed or hopeless?
- During the past month, have you often been bothered by having little interest or pleasure in doing things?
A positive answer to either of these questions suggests a degree of depression and requires further medical assessment.
Many factors have been implicated in depression, from genetic disposition and adverse early life experiences to social stress and elevated cortisol levels. Having a chronic physical illness increases the risk of depression and some prescribed medicines can cause depression.
Common examples include propranolol, interferon alfa, interleukin-2, mefloquine, corticosteroids and progestogen-releasing implanted contraceptives.
On a biochemical level a variety of neurotransmitter abnormalities have been hypothesised to contribute to depression. These include deficiencies in serotonin, noradrenaline, dopamine, gamma aminobutyric acid and peptide neurotransmitters.
National guidelines on the treatment of depression are available from the National Institute for Health and Clinical Excellence1 and the British Association of Psychopharmacology.2 The following recommendations are based on these guidelines.
Antidepressants are not initially recommended in mild depression that lasts less than three months. This is partly because the difference between the efficacy of placebo and active drug in this situation is small.
Non-drug therapies, such as cognitive behavioural therapy (CBT), a structured exercise programme or guided self-help, are preferred. CBT is the psychological intervention with the most supporting evidence. It explores how individuals feel about themselves and others, and how behaviour is related to these feelings.
CBT may also be used in moderate or severe depression, often in combination with an antidepressant. Guided self-help involves directing the sufferer to materials, such as computer programs, books or recordings, that may help address adverse feelings and thoughts.
They are usually based on CBT techniques and can be accessed at the patient’s convenience.
Antidepressants are recommended as first-line treatment for moderate and severe depression or mild depression that has persisted for longer than three months. In general, all antidepressants are as effective as each other in a first episode of depression and up to 60 per cent of patients show a response within the first two weeks of treatment.3
All antidepressants, with the exception of agomelatine (which is expected to be launched this month), increase the transmission of monoamines, particularly serotonin, noradrenaline and dopamine. Most achieve this by inhibiting the transporter responsible for the reuptake of serotonin or noradrenaline.
Monoamine-oxidase inhibitors (MAOIs), however, irreversibly block the enzyme monoamine oxidase, which, in turn, reduces the breakdown of serotonin, noradrenaline and dopamine.
Mirtazapine is an alpha2-adrenoreceptor antagonist that increases noradrenaline and serotonin transmission by reducing the action of the alpha2-adrenoreceptor negative feedback pathway.
Agomelatine causes 5-HT2c and 5-HT2b antagonism and is a direct agonist at melatonin 1 and 2 receptors. Its place in antidepressant therapy is unclear but the drug is likely to improve sleep and appears not to cause weight gain or sexual dysfunction, which are often adverse effects of other antidepressants.
Selective serotonin reuptake inhibitors
The selective serotonin reuptake inhibitors (SSRIs; ie, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) are recommended as first-line antidepressants because of their safety in overdose and tolerability compared with tricyclic antidepressants (TCAs).
They have similar mechanisms of action and side effect profiles but differ in their half-life, potential for interactions and cost. Fluvoxamine is rarely used in practice because it usually requires twice daily dosing and has multiple interactions. Paroxetine use has also declined recently because of its association with a higher rate of discontinuation symptoms.
Common initial adverse effects of the SSRIs include nausea, vomiting, diarrhoea and insomnia. Sexual dysfunction (eg, impotence, loss of libido) has also been reported in up to 70 per cent of patients taking SSRIs and this often persists throughout treatment,4 although sexual dysfunction can occur in depression in the absence of an antidepressant.
Two SSRIs that can cause confusion are citalopram and escitalopram. Citalopram consists of both R-citalopram (the inactive enantiomer) and S-citalopram (the active enantiomer). Escitalopram is the pure S-enantiomer.
There is some evidence suggesting that the R-enantiomer deactivates the S-enantiomer so escitalopram would be expected to be more effective than citalopram. Although this was met with initial scepticism there is mounting evidence that this is the case.5
In depression SSRIs are usually started at a therapeutic dose, with no need to titrate up. In patients with concurrent anxiety symptoms, however, it is useful to start at half the normal dose for a few weeks to prevent a worsening of anxiety symptoms (see PJ 1 November 2008, pp511–4).
If a patient fails to show any response to the first SSRI within four weeks or it is not tolerated, then switching to an alternative SSRI is recommended.1,2
Although SSRIs are similar in action, research has shown that up to one in four patients may improve after switching to a second SSRI.6
If there has been a partial improvement over the four weeks then continuing for another two weeks to assess any further response is appropriate.2
If both an initial and second SSRI are not effective or not tolerated, then switching to another antidepressant, such as mirtazapine, a TCA (excluding dosulepin), moclobemide or reboxetine, is recommended by NICE.1
TCAs (eg, amitriptyline, nortriptyline, clomipramine, dosulepin and lofepramine) may be useful where sedation is required but have other adverse effects, such as postural hypotension, blurred vision, urinary retention and weight gain.
Of particular concern are their many adverse effects on cardiac function, which means they should be avoided in anyone with an underlying cardiac abnormality or in those at a high risk of overdose (eg, patients with a history of attempted overdose and those who are actively suicidal).
Dosulepin and amitriptyline are particularly toxic in overdose. The former is restricted by NICE for use by mental health specialists’ only.1 Lofepramine is less cardiotoxic than other TCAs.
Selective serotonin and noradrenaline reuptake inhibitors
Venlafaxine has an effect on both serotonin and noradrenaline reuptake. However, it inhibits serotonin reuptake at any dose while noradrenaline reuptake is only inhibited above 150mg/day.5
A significant, dose-related increase in blood pressure has been reported with this drug, particularly in doses above 200mg/day so regular monitoring is recommended.
At high doses there is some evidence for the efficacy of venlafaxine in treatment-resistant depression so it is recommended for those in whom treatment with two previous antidepressants has failed.1
Duloxetine is also a dual reuptake inhibitor that can increase blood pressure. Unlike venlafaxine however, it does not have robust evidence in treatment-resistant depression so its place in therapy remains unclear.
It does have an extended licence for use in diabetic peripheral neuropathy and depression so may be useful for those who have both disorders.
Mirtazapine indirectly increases noradrenaline and serotonin transmission by alpha2-adrenergic inhibition. It also blocks 5-HT2A, 5-HT3 and H1 receptors, which reduces the incidence of nausea, vomiting and sexual dysfunction seen with the SSRIs.
However, it commonly causes sedation and weight gain. Mirtazapine is often used if first-line antidepressants have been poorly tolerated or sedation is required.
Reboxetine is a noradrenaline reuptake inhibitor with little effect on other neurotransmitters. It may be useful where serotonergic enhancing antidepressants have failed or are poorly tolerated.
Insomnia, sweating, tachycardia and palpitations are commonly reported and caution is recommended when prescribing reboxetine in patients with cardiac disease.4
Trazodone’s exact mechanism of action is not understood but it appears to increase serotonin turnover. It may be useful where sedation is required or where depression presents with anxiety symptoms.
Nausea, vomiting, dizziness and headache are commonly reported as are postural hypotension and tachycardia.
Monoamine oxidase inhibitors
Monoamine oxidase inhibitors (MAOIs; ie, phenelzine, isocarboxazid and tranylcypromine) are restricted to specialist use only when other treatments have failed. They are difficult to use safely because of their many food and drug interactions.
Only individuals who are motivated and able to comply with dietary restrictions should be considered for treatment with an MAOI. Patients must adhere to a low-tyramine diet to avoid a potentially life-threatening hypertensive crisis.5
This includes avoiding most mature cheeses and yeast extracts. Moclobemide is a reversible MAOI so a restrictive diet is not necessary.
Switching between antidepressants can cause problems especially when changing from fluoxetine or an MAOI. Problems that can occur on switching include discontinuation symptoms, serotonin syndrome (see Panel 2) and pharmacokinetic interactions.
Panel 2: Serotonin syndrome
Serotonin syndrome is a potentially life-threatening but preventable adverse reaction. It can occur following an overdose of antidepressants, as a result of an interaction between antidepressants or during normal therapeutic use.
All antidepressants that enhance serotonin have been associated with serotonin syndrome as have many non-antidepressant drugs (eg, tramadol, linezolid, buspirone and lithium).
Symptoms range from mild diarrhoea, sweating and tremor to akathesia, ataxia, confusion and convulsions.
Treatment involves the immediate removal of the offending agent and administration of supportive therapy. Moderate to severe cases should receive immediate medical attention.
For example, fluoxetine inhibits the liver enzymes cytochrome P450 2D6 and CYP 3A4 so can double or triple levels of TCAs. When switching from fluoxetine to a TCA, fluoxetine should be slowly discontinued followed by a wash out period of at least four days before the TCA is introduced.
In other cases a cautious cross taper may be appropriate (eg, mirtazapine to an SSRI).4
Factors that must be considered before switching are:
- The speed at which the switch is needed
- The current dose of the first antidepressant
- The individual properties of the antidepressants
- Any previous withdrawal effects experienced5
It is often safer to withdraw the first antidepressant slowly over a number of weeks before gradually introducing the new antidepressant.
St John’s wort has been used to treat mild to moderate depression it should not be routinely recommended (see Panel 3).
Panel 3: St John’s wort
St. John’s wort (SJW) is a widely available herbal product often recommended and used to treat depression. The current evidence supporting SJW in depression however, is inconsistent and confusing. A pooled meta-analysis in 2005 concluded that SJW improved symptoms more than placebo and similarly to standard antidepressants in adults with mild to moderate depression.
In this analysis no benefit was seen in patients with a severe or a prolonged duration of depression.7Other studies have disputed any benefit.
Of particular concern is that there is no standard, licensed product available in the UK, so drug quality is questionable. Moreover, SJW is a potent inducer of some hepatic cytochrome P450 enzymes. Specifically it induces CYP 3A4 and 2C9.6
Switching between brands can alter the interaction potential and when patients stop taking SJW blood levels of interacting medicines may be increased, leading to toxicity.
Exactly how SJW works also remains unclear but, as with other antidepressants, withdrawal symptoms and serotonin syndrome have been reported. Caution must also be used when switching from SJW to conventional antidepressants.
For all these reasons, SJW is not approved for depression and should not be routinely recommended.
The chance of remission of symptoms decreases significantly following a failure to respond to the initial antidepressant choices. Augmenting antidepressants with another agent or combining antidepressants is a useful option but should only be attempted by mental health specialists with previous experience of treatment-resistant depression.
Augmenting the antidepressant with either lithium or tri-iodothyronine appears a useful option as does augmentation with an atypical antipsychotic (such as olanzapine or quetiapine) or CBT.2
Combining antidepressants with the aim to increase response by broadening pharmacological actions has received some interest.
Mirtazapine with either an SSRI or venlafaxine are the most common combinations used by specialists. Not all patients, however, will tolerate the combination and must be monitored for symptoms of serotonin syndrome.
Electroconvulsive therapy (ECT) remains an effective short-term treatment for resistant or life-threatening depression.8
Before administering ECT the patient receives a short–acting general anaesthetic (eg, propofol) and the muscle relaxant suxamethonium. Then, under the care of an experienced team consisting of an anaesthetist, psychiatrist and psychiatric nurse, an electric current is passed through the brain with the aim of inducing a seizure.
ECT is thought to be more effective and faster acting than antidepressants but up to one third of patients may suffer memory loss.8
The benefits of ECT are rarely prolonged so an antidepressant must also be prescribed to reduce the risk of a relapse.
Further factors that should be considered with antidepressant therapy include discontinuation symptoms and an increased risk of bleeding.
All antidepressants, when taken for six weeks or longer, can cause discontinuation symptoms. Although these are usually mild and self-limiting, abrupt discontinuation of antidepressants should be avoided except after a serious adverse event (eg, serotonin syndrome, hyponatraemia or acute mania).
Symptoms reported when discontinuing SSRIs include flu-like symptoms, dizziness and electric shock sensations.4
These typically peak within the first week of withdrawal and taper off after two to three weeks. Ideally antidepressants should be discontinued slowly over four or more weeks.4
Antidepressants with short half-lives (eg, paroxetine and venlafaxine) are associated with the most reports of discontinuation symptoms. Fluoxetine is less likely to cause discontinuation symptoms and can usually be stopped at 20mg/day.
Although antidepressants can cause problems on withdrawal, they are not associated with tolerance or cravings so are not thought to be addictive.
Increased risk of bleeding
All antidepressants that inhibit serotonin reuptake (ie, SSRIs, SNRIs and TCAs) are probably associated with an increased risk of bleeding, particularly in the upper gastrointestinal tract.9
The mechanism behind this is likely to be depletion of serotonin from platelets by blocking the serotonin reuptake transporters. In high risk patients (eg, those with a history of gastrointestinal bleeds, and long-term users of non-steroidal anti-inflammatory drugs) the addition of an acid-suppressing agent, such as a lansoprazole or omeprazole, is recommended.
Most antidepressants have also rarely been associated with causing hyponatraemia. All patients prescribed antidepressants should have baseline sodium levels taken and these should be repeated if any adverse symptoms (eg, dizziness, nausea, confusion, cramps and seizures) occur.
Older people, females and patients who are underweight are most at risk. Stopping the antidepressant immediately and considering switching to a different class is recommended.4
The role of the pharmacist
Most patients suffering from depression will be seen in primary care or in general hospitals, with only severe or resistant cases being referred to psychiatric services.
Community pharmacists and hospital pharmacists are, therefore, well placed to advise on depression both to help identify underlying symptoms and to ensure appropriate treatment is prescribed and managed.
Panel 4 lists basic advice that pharmacists can give to patients.
Panel 4: Advice for patients
- Antidepressants are an effective treatment for persistent mild, moderate or severe depression.
- As with all medicines, antidepressants can cause adverse reactions. Many initial adverse reactions, such as nausea, anxiety, insomnia and drowsiness, wear off within a few days. Others, such as sexual dysfunction, weight gain and sweating, may persist and should be discussed with a doctor or pharmacist.
- In a first episode of depression antidepressants should be continued for at least six months after the remission of symptoms to reduce the risk of a relapse. Following two or more recent depressive episodes a course of two years or longer is recommended.
- Antidepressants are not addictive but should be withdrawn slowly because discontinuation symptoms are possible. Missing even one dose of some antidepressants can cause discontinuation symptoms.
For more complex cases, advice can be sought from local community mental health teams, hospital liaison psychiatric services or local mental health trusts.
Psychiatric specialist pharmacists are becoming more common within these teams and are often an integrated part of the service advising on appropriate psychotropic choices, improving safety in medicines use and reviewing patient-centred issues.
Depression Alliance is the leading UK charity for those with depression (www.depressionalliance.org; tel 0845 123 23 20)
www.choiceandmedication.org.uk is a website developed by the United Kingdom Psychiatric Pharmacist Group offering peer-reviewed information about medicines used in mental illness
- National Institute for Health and Clinical Excellence. Depression (amended). Management of depression in primary and secondary care. Clinical guideline 23. Available at www.nice.org.uk (accessed on 16 February 2009).
- Anderson IM, Ferrier IN, Baldwin, RC Cowen PJ, Howard L, Lewis J, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines. Journal of Psychopharmacology 2008:22; 343–96.
- Posternak M, Zimmerman M. Is there a delay in the antidepressant effect? A meta-analysis. Journal of Clinical Psychiatry 2006;66:148–58.
- Taylor D, Carol P, Kerwin R. The Maudsley Prescribing Guidelines 9th Edition. London: Informa HealthCare; 2007.
- Bazire S. Psychotropic Drug Directory. Aberdeen: Health Communications; 2009.
- Rush J, Trivedi M, Wisniewski S, Stewart JW, Nierenberg AA, Thase ME, et al. Bupropion-SR, sertraline or venlaxaxine after failure of SSRIs for depression. New England Journal of Medicine 2006;354:1231–42.
- Linde K, Berner M, Egger M, Mulrow C. St John’s Wort for depression. Meta-analysis of randomised controlled trials. British Journal of Psychiatry 2005;186:99–107.
- National Institute for Health and Clinical Excellence. Guidance on the use of electroconvulsive therapy. Technology Appraisal 59. Available at www.nice.org.uk (accessed on 16 February 2009).
- Abajo F, Garcia-Rodriguez L. Risk of Upper Gastrointestinal tract bleeding associated with selective serotonin reuptake inhibitors and venlafaxine therapy. Archives of General Psychiatry 2008;65:795–803.
CPD articles are commissioned by The Journal and are not peer reviewed.
Action: practice points
Reading is only one way to undertake CPD and the Society will expect to see various approaches in a pharmacist’s CPD portfolio.
- Given the adverse effects of dosulepin on the heart, make sure any patients dispensed this drug do not have a heart condition.
- Talk to your staff about depression.
- Find out contact details for your local community mental health team.
For your work to be presented as CPD, you need to evaluate your reading and any other activities. Answer the following questions:
- What have you learnt?
- How has it added value to your practice? (Have you applied this learning or had any feedback?)
- What will you do now and how will this be achieved?