The management of depression

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.

Diagnosis

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).

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. 

Treatment options

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.

Non-drug treatments

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.

Pharmacotherapy

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-HT_2c and 5-HT_2b 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

Tricyclic antidepressants

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.

Other antidepressants

Mirtazapine indirectly increases noradrenaline and serotonin transmission by alpha₂-adrenergic inhibition. It also blocks 5-HT_2A, 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.

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).

Treatment-resistant depression

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

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.

Other considerations

Further factors that should be considered with antidepressant therapy include discontinuation symptoms and an increased risk of bleeding.

Discontinuation symptoms

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.

Hyponatraemia

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.

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.

References

1. 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).
2. 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.
3. Posternak M, Zimmerman M. Is there a delay in the antidepressant effect? A meta-analysis. Journal of Clinical Psychiatry 2006;66:148–58.
4. Taylor D, Carol P, Kerwin R. The Maudsley Prescribing Guidelines 9th Edition. London: Informa HealthCare; 2007.
5. Bazire S. Psychotropic Drug Directory. Aberdeen: Health Communications; 2009.
6. 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.
7. 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.
8. 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).
9. 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.