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The pharmacological treatment of depression
A thorough assessment of depression in older people is important. If left untreated depression can be associated with increased morbidity and mortality and can be exacerbated by physical illness. Professor Stephen Curran and Richard Clibbens examine the pharmacological approach to managing depression including new drugs such as selective serotonin re-uptake inhibitors and serotonin and noradrenaline re-uptake inhibitors.
An estimated 10-15 per cent of people aged over 65years will be experiencing depression at any given time1. However, depression in older people is frequently under-diagnosed and is often mistakenly seen by older people and their families as an inevitable part of growing older. High rates of depression have also been reported in patients with stroke, arthritis, and Parkinson's disease2 and older people with chronic illness are twice as likely to be depressed as the physically well.
Within the general hospital setting, 25-45 per cent of patients have clinically significant depression3.
Symptoms of depression include low mood, anhedonia (an inability to experience pleasure), sleep disturbance, poor appetite, weight loss, hopelessness, fatigue, and suicidal ideas4.
A US consensus meeting in 1992 found that depression in older people was under-recognized, associated with a suicide rate that was twice that of younger people and was strongly associated with physical illness5. However, the diagnosis of depression may be more difficult to make in older compared with younger people for a number of reasons. For example, older people with depression are more likely to have somatic complaints and might be more likely to be diagnosed as suffering from physical illness. Many of the features associated with physical illness, for example, insomnia, weight loss, fatigue, and poor appetite, are also seen in depression, making diagnosis more difficult. The presence of anhedonia can be helpful when trying to make a differential diagnosis. Older people are also more likely to have agitation which may be attributed to anxiety rather than depression.
Clues to the emergence of a depressive illness include the presence of new symptoms, for example, early morning wakening in the setting of sleep disturbance, and the presence of fatigue, even at rest. A family or personal history of depression, and a drug history are also important contributory factors and evidence for recent major life events should be sought. In addition, a full physical examination, including appropriate investigations, should form an integral part of the assessment as many physical illnesses can cause depression, e.g. hypothyroidism, dehydration and anaemias.
The National Service Framework for Older People (NSF)1 recommends that referral to a specialist mental-health service for older people should be considered if diagnosis is uncertain, there are complex symptoms, and if there is a suicide risk. Risk factors for suicide include:
There are a number of instruments that can be used to screen for depression. The Geriatric Depression Scale (GDS-30) is widely used and assesses mainly cognitive aspects of depression rather than physical symptoms. It can be administered relatively quickly, with a score of greater than or equal to 11 being suggestive of depression6. As well as being a useful screening instrument for depression, it can also be used to monitor response to treatment. Shorter forms are also available (e.g. GDS-15) which are quicker to administer but they give a less comprehensive assessment compared with longer forms.
There are many causes of depression and treatment of the underlying cause is often the most effective way to treat the depression. Biological factors increasing the risk of depression include:
Physical illness can predispose to, precipitate, or perpetuate depression. A number of different aspects of physical illness can act as vulnerability factors for depression, including pain, disability, poor diet and reduced physical activity. Physical illness is also associated with greater morbidity and mortality in older people with depression7.
Drugs may also frequently cause depression including benzodiazepines, anti-Parkinsonian drugs (e.g. anticholinergics and levodopa), cardiovascular drugs (e.g. b-blockers, enalapril), gastrointestinal drugs (e.g. cimetidine, ranitidine), non-steroidal anti-inflammatory drugs (NSAIDs), respiratory drugs (e.g. aminophylline and theophylline) and steroids8. Social factors such as reduced social networks, loneliness, and bereavement all increase the risk of depression developing.
Depression can be treated using a range of different approaches including general support, problem-solving, formal psychological techniques, pharmacotherapy, and electroconvulsive therapy (ECT). Appropriate and effective treatment is important because depression in older people is associated with a high morbidity and mortality. The treatment of depression should also include treatment of any underlying physical illness, whether directly or indirectly related to the depression. Strategies for recovery from depression should also include enhancing social networks and support.
Primary care has an essential role in the early detection, assessment and treatment of depression in older people but where available, specialist mental-health liaison staff can provide a range of interventions within the general hospital setting. This includes individual patient assessment, monitoring, and discharge planning. The provision of education or joint-working with hospital teams to develop mood assessment, care and treatment skills may be particularly useful. The NSF identifies the need for professionals working with older people in general hospital settings to develop appropriate assessment and interventions for depression, in addition to a clear role for specialist mental-health services in providing assessment of more complex cases and a liaison, education, and consultancy role to general hospital teams.
The NSF also notes that good clinical care of older people on general medical and surgical wards will involve attention to depression. Depression in later life is frequently not treated at all or under-treated. The NSF recommends that treatment with antidepressants should involve adequate doses (BNF limits) and should be given for 'a minimum of 6weeks'. Some authors have suggested treating older people for at least 12 weeks5 but once a patient has recovered, treatment should be continued for at least 6 months9. Nurses are ideally placed to monitor the clinical benefits and side-effects of antidepressants within the general hospital environment.
All antidepressants 'work' by interacting with the noradrenergic and/or serotoninergic systems to varying degrees, and their different mechanisms of action largely explains their different side-effect profiles. Side-effects may be more serious with the older antidepressants [e.g. tricyclic antidepressants (TCAs) compared with newer drugs, and include sedation, anti-cholinergic effects (blurred vision, confusion, urinary retention, exacerbation of glaucoma), cardiotoxicity, and a greater propensity to induce convulsions. The newer drugs, such as selective serotonin re-uptake inhibitors (SSRIs; fluvoxamine, sertraline, fluoxetine, paroxetine and citalopram), serotonin and noradrenaline re-uptake inhibitors (SNRIs; venlafaxine), and noradrenaline re-uptake inhibitors (NARIs) are better tolerated, have fewer side-effects, are safer in overdose, and are less likely to cause convulsions compared with TCAs9.
The efficacy of TCAs in the treatment of depression is well-established and there is evidence that the class is more effective than the SSRIs in treating patients with severe depression that is characterized by:
There are a wide range of TCAs with variable half-lives, for example, amitriptyline (9 to 46 hours), and imipramine (6 to 28 hours). For this reason, TCAs may have to be given more than once per day, depending on the response of the individual patients. Side-effects are also quite extensive and in general, these drugs are less acceptable to older patients. Side-effects include anti-cholinergic side-effects such as blurred vision, urinary retention, constipation, and dry mouth. They can also impair memory, which may be a serious problem for older patients with early dementia. Care also needs to be taken with patients with compromised cardiovascular function. Cardiovascular problems include orthostatic hypotension and an increased risk of cardiac arrhythmias. There is also a risk of heart block and careful monitoring with EEG may be needed.
TCAs may also occasionally cause increases in liver enzymes and cause delirium probably through anticholinergic mechanisms. Many TCAs are very sedating, which may be associated with falls and they are potentially fatal in overdose. For this reason, the starting dose should normally be small and gradually increased over several weeks. Lofepramine is not sedative, it has relatively few anticholinergic or cardiac side-effects, and is the most commonly prescribed TCA in older people. However, it does have a propensity to cause constipation and orthostatic hypotension.
These drugs have been available for several decades but are seldom used because of the risk of a hypertensive crisis if taken with foods containing tyramine. However, a relatively recent meta-analysis found that MAOIs were effective in 53 per cent of in-patients and 57 per cent of out-patients with depression11. They are not usually used as a first-line treatment but have tended to be prescribed for the management of treatment resistant depression and for patients with atypical symptoms. These drugs (e.g. phenelzine and tranylcypromine) act by inhibiting monoamine oxidase, an enzyme responsible for the breakdown of noradrenaline and serotonin. If the patient is switched to another antidepressant, a wash-out period of at least two weeks is advisable because of the risk of severe hypertension. Side-effects can be serious and include:
Because of the risk of a hypertensive crisis, patients have to observe a strict diet and foods rich in tyramine should be avoided (e.g. cheeses, certain alcoholic beverages, yeast products, and game).
SSRIs (e.g. paroxetine, fluoxetine, citalopram, and sertraline) are now commonly prescribed for depression in older people. Between 1993 and 1997 in Ontario, the proportion of older people being treated with antidepressants rose from 9.3 per cent to 11.5 per cent and during the same period the proportion being prescribed an SSRI increased from 9.6 per cent to 45.1per cent12.
The SSRIs have some advantages over TCAs and MAOIs. In particular, they have less sedation, postural hypotension and anticholinergic side-effects. They are also safer in overdose and are associated with a lower incidence of seizures. They are also effective in the treatment of depression and are well tolerated in older people13.
These drugs work by blocking serotonin re-uptake from the synaptic cleft into the pre-synaptic neurone, thereby increasing the concentration of serotonin in the synaptic space. Patients can usually be started on the therapeutic dose unlike the TCAs and MAOIs which have to be gradually titrated to avoid unpleasant and potentially serious side-effects. The commonest side-effects include dizziness, dry mouth, sweating, anxiety/agitation, drowsiness, nausea, and diarrhoea. These tend to be worse during the early phase of treatment and subside after a couple of weeks or so. Sometimes, giving the patient a small dose for a few days will avoid these problems.
Moclobemide, a reversible inhibitor of monoamine oxidase A (RIMA) is only indicated for major depression. It causes less potentiation of the pressor effects of tyramine but patients should still avoid eating large amounts of tyramine-rich food. Although the risk of interactions with other drugs is less than with MAOIs, sympathomimetics, for example, ephedrine, should still be avoided. In addition, moclobemide should not be given with another antidepressant. Because of its short half-life, no treatment-free period is required after it has been stopped. However, if the patient is switched to moclobemide from another antidepressant the moclobemide should not be started until five times the half-life of the first antidepressant has elapsed. It has a number of side-effects including sleep disturbance, dizziness, nausea, headache, agitation, and confusional state. However, it is well tolerated in the elderly and may be a useful alternative for depressed patients with prominent anxiety and an absence of melancholic features14. Moclobemide is also safe in overdose.
The principle antidepressant in this class is venlafaxine. This drug is indicated for depression and generalized anxiety disorder. It works by blocking the re-uptake of both serotonin and noradrenaline from the synaptic cleft and thus increases the availability of both these neurotransmitters. The main side-effects include nausea, dizziness, dry mouth, insomnia, nervousness, headache and constipation, and these tend to be dose-dependent. Venlafaxine is safe in overdose and has a low propensity to induce seizures compared with the TCAs.
Selective NARIs are a new class of antidepressant which specifically target the re-uptake of noradrenaline. The best known example is reboxetine. It has been extensively studied in depression and is as effective as the TCAs and fluoxetine15. It is claimed to have a greater effect on social functioning compared with other antidepressants. Side-effects include vertigo, tachycardia, impotence, urinary retention, insomnia, increased sweating, constipation and dry mouth. The frequency of these is low, and for many there is no significant difference from placebo. The seizure rate is also very low.
Mirtazapine (NaSSA) is a new class of antidepressant. This is a selective pre-synaptic a2-adrenoceptor antagonist that increases synaptic availability of noradrenaline. It also blocks 5-HT2 and 5-HT3 receptors and thus enhances transmission of 5-HT1 receptors, which have been associated with anxiolytic properties. It has a half-life of approximately 43 hours and can thus be given once daily. Side-effects include dry mouth, drowsiness, increased appetite, and weight gain, but these are significantly less than with TCAs. The reported incidence of seizure is very low and this figure is not significantly different from placebo. The available data suggest that it is safe in overdose.
The recovery rate for an individual episode of depressive illness is good and 75 per cent to 80per cent will improve over a 6-month period. In the longer term, only about 25 per cent will remain completely well. These patients are usually 'quick responders' as well as being physically healthy. For approximately 60 per cent of all patients, the prognosis in the longer term is 'quite good', in that they will either remain well or have relapses which can be successfully treated. A small proportion of patients with depression remain resistant to all conventional therapies. Even after recovery, relapses are common and tend to occur relatively early on. Two-thirds of these occur within the first 18 months so careful follow-up is essential. Adverse prognostic factors include poor response to treatment, serious physical illness (at initial contact or during follow-up), long duration of illness prior to presentation, and the presence of delusions16.
Depression in older people is common. Many factors can contribute to the development of depression including life events, social factors, and physical illness. It is therefore important to undertake a detailed psychological, social, and physical assessment to identify all the possible contributory factors. It is particularly important to ask the patient about suicidal ideas.
Depression in older people responds to treatment. A pharmacological approach is more likely to be effective if the patient has biological symptoms such as anhedonia, sleep disturbance, diurnal variation of mood, and weight loss. It is important to ensure that the patient is given an adequate dose for an adequate period, and response to treatment may take as long as 12 weeks. No single pharmacological treatment is suitable for all patients on all occasions. It is therefore important to choose the most appropriate treatment for each patient and factors to consider include previous response to treatment, concurrent physical illness and practical issues such as an inability to swallow tablets.
The newer drugs such as the SSRIs and SNRIs are better tolerated and safer in overdose compared with TCAs but these drugs can also be associated with side-effects, especially gastrointestinal. Although the focus of this article has been on pharmacological treatments, social and psychological interventions are equally important in managing depression in older people.
Stephen Curran is Professor of Old Age
Psychopharmacology, School of Human and Health
Sciences, University of Huddersfield, and is also
Consultant in Old Age Psychiatry and Richard Clibbens is Nurse Consultant, South West Yorkshire Mental Health NHS Trust, Fieldhead Hospital, Wakefield
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