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Depression and its treatment: a team effort

Russell Greene
BPharm MSc PhD MRPharmS
Senior Lecturer in Clinical Pharmacy Department of Pharmacy
School of Health and Life Sciences
King's College London
E:russell.greene@kcl.ac.uk

Most of us experience a depressed mood from time to time. Feelings of sadness are regarded as normal responses to a recent loss or disappointment, and they usually remit spontaneously.
 
How then is this distinguished from an illness? When does a sufferer become a potential patient requiring intervention? One answer is, when the depression is socially incapacitating or the patient cannot cope. Another example might be someone who is obviously severely depressed without evident reason. It is also necessary to consider possible medical or iatrogenic causes of the depression.

Depression is surprisingly common, and much goes unreported partly because of the social stigma of mental illness. Even when diagnosed it is frequently inadequately treated. Finally, even when treatment is apparently adequate, many patients do not comply with their medication

This article looks at the clinical features of depression and how, with the cooperation of all the healthcare team, drug therapy can be optimised.

What is depression?
The cardinal symptom of depression is low mood, but other features depend on the precise type. There are several ways of classifying depression, but for practical purposes it is best to consider severity and tendency for recurrence. At one end we have a single minor depressive episode, probably in response to a difficult life event such as bereavement. At the other is the patient with recurrent severe depressive illness with no apparent cause. Clearly these cases require different management strategies.

Core features even in minor depression include pessimism and loss of the capacity for enjoyment (anhedonia) and the ability to concentrate (see Figure 1). If depression is more severe, other symptoms appear. In moderate depression there may be insomnia, irritability (labile mood), demotivation, apathy and deliberate self-harm. In yet more severe cases there may be physical (somatic or "biological") signs such as agitation or retardation. A very characteristic feature is a fixed daily mood variation regardless of what happens to the patient: the sufferer wakes early feeling very low, the mood improving a little by evening.

[[NIP09_fig1_17]]
 
In very severe cases (major depression) there may be psychotic features such as diminished insight, delusions of guilt and worthlessness, and occasionally even hallucinations (usually voices accusing the sufferer of letting people down or being "bad"). These cases present the most serious risk of carefully planned, often completed suicide. This was formerly called "endogenous depression" because there is frequently no obvious external cause; it comes from within.
 
Depression may be accompanied by additional features such as anxiety, self-pity and anorexia and by psychosomatic symptoms (somatisations) such as gastrointestinal upsets, constipation, palpitations or rashes. In manic-depressive disorder there are alternating phases of major depression and mania (abnormally elevated mood). "Mixed affective disorder" is a syndrome commonly seen in primary care: the patient shows simultaneous signs of both anxiety and mild depression.
 
About 20% of us develop a depressive episode at some stage in our life, a quarter of cases becoming chronically recurrent. About one in 10 of GP consultations involve depression: only one in 20 cases is referred to secondary care. Depression is about three times more common in women, and its prevalence increases with age.
 
Management
Key factors in managing depression are to identify any suicidal tendency; eliminate possible underlying causes such as chronic illness (eg, hypothyroidism) or certain drug therapies (eg, methyldopa); treat the current episode vigorously; and consider prophylaxis. A multidisciplinary team approach involving clinicians, nurses, psychologists, social workers and pharmacists is preferred. The three main types of treatment are psychotherapy, drugs and ECT (electroconvulsive therapy).

Psychotherapy
Psychotherapy (notably cognitive behavioural therapy) may be particularly useful for the milder forms, but is clearly inappropriate for severely depressed, retarded patients lacking insight. In these latter cases drugs or ECT are almost invariably indicated, especially where biological or psychotic features are prominent. Temporary custody and involuntary treatment under a section of the Mental Health Act may even be required, to prevent patients harming themselves or making unwise decisions.

Drugs
Drugs are the mainstay for the majority of patients at all levels of severity. Used correctly they are safe, effective and relatively cheap. However, as we shall see, they are commonly not used correctly. ECT is used for severely ill patients to bring about a more prompt resolution of profound symptoms than can be achieved by drugs; this can be literally lifesaving in the suicidally depressed.
 
Antidepressant drugs may be considered in three groups: the tricyclic and related second-generation antidepressants; the monoamine oxidase inhibitors (MAOIs); and the more recent selective serotonin reuptake inhibitors (SSRIs). All work by interacting with the neurotransmitters that are involved with the control of mood (chiefly serotonin [5HT] and noradrenaline).
 
Contrary to a prevailing public misconception, none is in any way addictive or dependence-producing. Most antidepressants need be given only once daily, which improves compliance. However, a drawback common to all is a 2-4-week lag before any noticeable improvement in mood, which may severely diminish the patient's confidence in the medication if not carefully explained. Unfortunately, adverse effects may be experienced much earlier. Many patients only reluctantly concede they are ill, and compliance - poor anyway - may be reduced if results are not seen soon but unexpected side-effects are.

Tricyclic antidepressants
These were the first drugs found specifically to elevate mood, and they are still widely used (see Table 1). Newer developments offer the advantage only of reduced adverse effects: none is superior to amitriptyline in antidepressant effectiveness. Tricyclics are also usually cheapest.

[[NIP09_table1_18]]

Their main drawback is adverse effects. Because they affect a wide range of neurotransmitters they can cause problems in the autonomic nervous system, principally anticholinergic symptoms such as dry mouth, blurred vision, constipation, urinary retention, hypotension and tachycardia. Amitriptyline in particular can be sedative, which, while it may be beneficial for accompanying anxiety, can be troublesome, especially in the elderly; as a result it is best taken at night.

These effects are uncomfortable but not especially dangerous, except in certain patient groups (eg, retention in prostatic hyperplasia). Gradual dose escalation minimises the problems and they diminish with time. More serious are arrhythmogenic and convulsive actions when taken in overdose, particularly as they are being used by patients at high risk of self-harm or suicide. Specific antidotes do not exist, and there is significant mortality.

To be effective these drugs must be prescribed at the equivalent of 125-150mg amitriptyline nightly, and this is frequently not observed. Lower doses may be sedative but are not antidepressant. A three-times-daily dose of 25mg is ineffective (and still causes adverse effects!).

Second-generation antidepressants
Subsequent developments (Table 2) sought to improve the adverse effect profile. There may be fewer autonomic effects (eg, doxepin, venlafaxine), less cardiotoxicity (eg, reboxetine), less convulsant action (mianserin) or less sedation (eg, lofepramine).

[[NIP09_table2_18]]

Selective serotonin reuptake inhibitors
These drugs were specifically developed to target one single transmitter (Table 3). Although they are no more effective then earlier drugs they have far fewer adverse effects. Thus they are far safer in overdose and lack anticholinergic action. Their main problems are excessive CNS stimulation (anxiety, agitation) and minor GI disorders (dyspepsia, nausea, altered bowel function). The CNS effects can become prominent if treatment is withdrawn too abruptly (although this can happen with the other antidepressants too). Dosage is simpler because escalation is unnecessary - they can be started at near the normal effective dose. They are, however, expensive.

[[NIP09_table3_18]]

Monoamine oxidase inhibitors
These drugs (Table 4), although cheap and effective, have acquired an unenviable reputation because of the "cheese reaction". Tyramine, a constituent of cheese, red wine, certain pickles, etc, is normally destroyed in the GI wall by monoamine oxidase. In patients whose monoamine oxidase is inhibited, tyramine is absorbed unchanged, potentially leading to a dangerous hypertensive reaction, which is occasionally fatal. Consequently, these drugs are usually prescribed by secondary care specialists, and pharmacists issue a warning card. A new version, moclobemide, does not cause this reaction and is safer to use. Although in general this group offers no major advantages, it can be useful second line for patients resistant to other drugs.

[[NIP09_table4_19]]

Practice issues
A distinction must be made between a single depressive episode, related to a traumatic life event and unlikely to recur, and recurrent depressive illness. Figure 2 shows the treatment stages. For all but the SSRIs the dose is started low to enable patients to adjust to adverse effects, then increased gradually over two weeks. Remission may take up to three months, but treatment should continue for a further six months. For a single isolated episode this should suffice, but if the patient had a previous episode carers should discuss with them the option of low-dose prophylaxis for up to three years. Discontinuation should always be gradual and not abrupt, especially with the SSRIs.

[[NIP09_fig2_19]]

Antidepressant treatment has a high dropout rate, from poor compliance, premature cessation and adverse effects that have not been fully explained. Points that should be discussed with patients are included in Table 5, which also covers some prescribing issues. Clinicians, nurses and pharmacists all have a role to play reinforcing these messages when the medication is started and throughout the course of therapy.

[[NIP09_pp_19]]

Further reading

  1. Doris A, Ebmeier K, Shajahan P. Depressive illness. Lancet 1999;354:1369-75.
  2. Spigset O, Martensson B. Drug treatment of depression. BMJ 1999;318:1188-91.
  3. Donaghue J, Katona C, Tylee A. Treatment of depression: antidepressant prescribing for the elderly in primary care. Pharm J 1998;260:500-2.
  4. Ewan M, Greene R. Evaluation of mental health care interventions made by three community pharmacists -a pilot study. Int J Pharm Pract 2001;225:225-34.

Resources
MIND
W:www.mind.org.uk

Depression Alliance
W:www.depression alliance.org