myoclonus and ataxia. Treatment of the syndrome .... Orthostatic. Cardiac. Risk of fatality in ergic ... myoclonus, changes in blood pressure). Stopping treatment.
Drug review Depression
Current approaches to the drug treatment of depression Alexander Galloway MB ChB, Steve MacGillivray MA, RMN and Ian Reid PhD, MRCPsych Skyline Imaging
Depression is the most common and costly mental health problem seen in general practice1 and the mainstay of treatment remains the use of antidepressants. Our Drug review considers the properties of the drugs currently available and current prescribing guidelines. This is followed by further sources of information in Resources, an analysis of prescription data and details of the drugs available in the Datafile. www.escriber.com
any effective drug treatments for depression are readily available to practitioners and the prognosis for adequately treated patients is good. Although psychological therapies have been demonstrated to be effective in the management of depression (cognitive and behavioural therapy in particular),2,3 the lack of highly trained therapists means that the majority of patients are treated with antidepressant drugs alone. Up to 40 per cent of depressed patients fail to demonstrate a response to first-line antidepressant drug treatment,4 and of those that do respond only a proportion will achieve full recover y. 5 Compounding these problems, the prescribing of antidepressant drugs in general practice may not
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Depression
A definition of a depressive episode includes the presence of some or all of the 10 symptoms listed below that have been present for at least two weeks. Four symptoms indicate a mild episode, six symptoms a moderate episode and eight a severe episode. In order to make the diagnosis one of the first two symptoms in the list must be present. Other symptoms that may be present include psychotic symptoms, such as hallucinations or delusions. Regardless of how many symptoms are present, if hallucinations or delusions are present the episode is severe. 1. depressed mood 2. loss of interest 3. decreased energy 4. loss of confidence or self-esteem 5. inappropriate guilt or self-reproach 6. suicidal thoughts or behaviour 7. poor concentration 8. psychomotor retardation or agitation 9. sleep disturbance (increased or decreased) 10. change in appetite Table 1. ICD-10 diagnostic criteria for a major depressive episode
conform to evidence-based clinical guidelines,6,7 and patient noncompliance with prescribed medication remains a major cause for concern.8 In consequence, treatment response is often incomplete, relapse is common and the risk of developing more chronic forms of depression is increased.9 Table 1 indicates the ICD-10 criteria for a major depressive episode. Drugs available to treat the condition
There are many different antidepressants available in the UK, each of which can be classified into one of eight categories defined by their mechanism of action. The pathophysiology of depressive illness is not yet fully understood. Antidepressants exert their effects on different neurotransmitter systems – mainly serotonergic (5-HT), noradrenergic and dopaminergic. The ‘biogenic-amine theory’ of depression suggests that it is caused by a reduction in function of any or all of these neurotransmitters at postsynaptic receptors. This leads in turn to intracellular changes that affect neuronal health. Antidepressants act to reverse these changes by strengthening monoamine neurotransmission, generally by blocking monoamine reuptake from the synapse by the releasing neurone and thereby, via a poorly understood chain of events, potentiating postsynaptic activity. Hence, for example, the designation selective serotonin ‘reuptake’ inhibitor (SSRI). Table 2 highlights the differential receptor profiles of the more commonly used antidepressants in pri42
Prescriber 19 January 2006
mary care and also includes details of the half-lives of each drug. Of note is the relatively long half-life of fluoxetine (Prozac) which, while being useful in allowing for continued efficacy despite missed doses, can pose problems for switching treatments since a longer washout period may be required. Efficacy Generally speaking all antidepressants are thought to have approximately equal efficacy. There are in excess of 400 randomised, placebo-controlled trials of acute treatment efficacy. Regardless of the specific mechanism of action, these studies result in 60-70 per cent of patients responding to active treatment and 30-40 per cent to placebo. Trials comparing antidepressants head-to-head, eg SSRIs with TCAs, tend to find approximately equal efficacy, particularly when data are collated in meta-analyses.10-12 Newer antidepressants including SSRIs and related types (selective noradrenaline reuptake inhibitors – SNRIs – and noradrenaline reuptake inhibitors – NARIs) are better tolerated and safer than either tricyclics or MAOIs, which can lead to cardiotoxicity or CNS depression in overdosage. There is still a role for MAOIs in cases of treatment-resistant depression, defined as depression unresponsive to two or more antidepressants given at an adequate dose for an adequate time. Current NICE guidelines suggest that phenelzine (Nardil) should be considered in patients who are prepared to tolerate the side-effects and dietary restrictions. Antidepressants may be effectively used in conditions other than depressive disorder including a range of anxiety disorders, obsessive-compulsive disorder and chronic pain. The evidence for differential efficacy of different antidepressants in these disorders is limited, but licensing arrangements do vary. Many of these conditions are often co-morbid with depressive disorder. Table 3 highlights the different recommended uses for the most commonly used antidepressants. St John’s wort Hypericum perforatum (St John’s wort) is a herbal health product sold over the counter as an alternative treatment for depression. Along with other herbal remedies and supplements it has become increasingly popular in the UK and is used by up to 12 per cent of the adult population in the USA.13 Meta-analysis of its efficacy in depression has been inconclusive.14 A randomised, controlled, double-blind trial15 of Hypericum perforatum vs paroxetine (Seroxat) in 251 patients has recently been published. The results suggest that it is www.escriber.com
Depression
at least as effective as paroxetine and better tolerated. Hypericum perforatum interacts with other medications to a significant degree through inducing cytochrome 3A.16 It can decrease bioavailability of drugs including digoxin (Lanoxin), warfarin (Marevan), the oral contraceptive pill, methadone (Physeptone) and statins. Compounding this is the inconsistency of preparations and the fact that most patients do not reveal their use of herbal supplements to medical practitioners.13 Current NICE guidelines do not recommend the use of St John’s wort. Side-effects While all antidepressant drugs can and often do cause side-effects, the most serious occur rarely. The most serious effects caused by TCAs concern cardiac conduction disturbances, particularly in overdose. Antidepressants with mainly serotonergic (5-HT) activity have the potential to cause an insidious and potentially fatal serotonin syndrome. Serotonin syndrome is usually caused by an increase in the dose of a serotonergic antidepressant or by the additional use of another serotonergic drug or MAOI. Findings suggest that about 10 per cent of overdoses with SSRIs may result in the syndrome. Other research suggests that the syndrome may exist Antidepressant
in mild form in a large proportion of patients. Symptoms overlap with both typical side-effects and/or with neuroleptic malignant syndrome, which can make diagnosis difficult. Onset is usually rapid (within 24 hours) and patients usually present with cognitive impairment (disorientation, confusion), fever, shivering, diarrhoea, agitation, restlessness, myoclonus and ataxia. Treatment of the syndrome includes immediate discontinuation of the serotonergic drug/s and the maintenance of adequate hydration and cardiac and renal function. After discontinuation of the drug/s the syndrome usually resolves within 24 hours. Sexual dysfunction (failure of erection in men, anorgasmia in women) is common with most antidepressant drugs (particularly the SSRIs but also the TCAs), and is a common and probably underreported cause of noncompliance. The problem is likely to be caused by actions on the serotonergic system. For some patients spontaneous resolution will occur, while for those that continue to suffer, there is some limited evidence that the NARI reboxetine (Edronax) is preferable to paroxetine in avoiding sexual dysfunction in both men and women.17 However due to the relative lack of data on the side-effects of reboxetine, NICE guidelines highlight the need for careful monitoring.
Half-life (hours)
Receptor profile Serotonin (5-HT)
Noradrenaline
Dopamine
Tricyclics amitriptyline clomipramine dosulepin lofepramine
8-24 17-28 14-40 2-5
+++ +++ + +
++++ + + ++++
+ O + O
SSRIs citalopram escitalopram fluoxetine paroxetine sertraline
33 27-32 24-140 24 25-26
++++ ++++ ++++ ++++ +++
O O O O O
O O + O O
Other duloxetine venlafaxine
8-17 1-2
++++ +++
++++ +++
+ +
O = no effect; + = minimal effect; ++ = minor effect; +++ = moderate effect; ++++ = marked effect Table 2. Half-lives and receptor profiles of the most commonly used antidepressants in primary care www.escriber.com
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Depression
Depressive illness
SSRIs citalopram escitalopram fluoxetine fluvoxamine paroxetine sertraline
Tricyclics amitriptyline clomipramine dosulepin lofepramine imipramine
Other venlafaxine
Panic disorder
Obsessivecompulsive disorder
Social phobia
Generalised anxiety disorder
Posttraumatic stress disorder
Bulimia nervosa
Table 3. Licensed uses of the most commonly prescribed antidepressants
Table 4 gives the more commonly occurring sideeffect profiles of the available antidepressants. Most of these side-effects are transient and they usually subside within the first few weeks of treatment. Clearly profiles differ, with TCAs being more likely to cause sedation, anticholinergic effects and hypotensive problems than the SSRIs. SSRIs, on the other hand, may cause intolerable nausea and headache. Suicide risk with SSRIs A possible link between certain SSRIs and suicide, in particular paroxetine, has been well publicised.18 In 2004, the European Medicines Agency (EMEA) concluded that although rates of suicidal behaviour and hostility were increased in children and adolescents, the overall benefit-risk of paroxetine remained positive. A study with over 40 000 participants19 concluded that there was weak evidence for an increased risk of self-harm with SSRIs. However, due to the low incidence of suicide and a lack of individual patient evidence, an increased risk could not be completely ruled out.19 There is a need for further research to clarify the degree of risk and which individuals may be most affected. Both EMEA and current NICE guidelines recommend more frequent monitoring of younger patients who commence antidepressant medication (see Table 5). www.escriber.com
Withdrawal of antidepressants Discontinuation or withdrawal symptoms including dizziness, nausea, paraesthesia and headaches can occur transiently when antidepressant treatment is reduced, missed or stopped. These are typically mild though they can be extremely distressing. This is a particular problem if patients miss doses of medications with shorter half-lives such as paroxetine. NICE recommends that patients should be informed of these potential problems in advance. Should they occur, medication should be restarted at the previous effective dose and then withdrawn more gradually while monitoring symptoms. Drug interactions Many drugs can interact with antidepressants causing an increase in toxicity/side-effects and/or a reduction in efficacy. Since all antidepressants are highly bound to plasma albumin, any drug that causes displacement from this binding – eg phenytoin (Epanutin), aspirin, antipsychotics and oral anticoagulants – may increase the likelihood or intensity of side-effects/toxicity. Any drugs that interfere with the hepatic metabolism of antidepressants, eg cimetidine, antipsychotics, steroids, oral contraceptives and alcohol, may result in increased blood concentrations of the antidepressant due to slowing of elimination. Thyroid hormone, if used in combination with an antidepressant, can increase the therapeutic effects of the Prescriber 19 January 2006
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Depression
Antidepressant
Sedation
Anticholinergic
Nausea
Orthostatic hypotension
Cardiac effects
Risk of fatality in overdose
SSRIs citalopram escitalopram fluoxetine fluvoxamine paroxetine sertraline
O O O + O O
O O O + O O
++ ++ ++ +++ ++ ++
O O O O O O
O O O O O O
+ + O O O O
Tricyclics amitriptyline clomipramine dosulepin doxepin imipramine lofepramine trimipramine
+++ ++ +++ ++ + + ++
+++ +++ ++ + ++ ++ +++
++ ++ O + ++ + +
++ + ++ ++ +++ + ++
+++ ++ ++ ++ ++ + ++
+++ + +++ ++ +++ O ++
Related trazodone
++
+
+++
++
+
O
NaSSA mirtazapine
++
O
O
+
O
O
SNRI venlafaxine
+
O
++
O
++
?
NARI reboxetine
O
+
+
O
+
O
MAOI phenelzine
O
+
++
+++
+
++
RIMA moclobemide
O
+
+
+
O
O
NaSSA = noradrenergic and specific serotonergic antidepressant; SNRI = selective noradrenaline reuptake inhibitor; NARI = noradrenaline reuptake inhibitor; MAOI = monoamine oxidase inhibitor; RIMA = reversible inhibitor of monoamine O = little or no effect; + = low effect; ++ = moderate; +++ = high Table 4. Relative side-effects (at average dose) of selected antidepressants
antidepressant but is equally likely to increase the toxicity of both drugs. Costs of treatment
The costs associated with depressive disorders are considerable, not least because of the high prevalence of the disorder. Up to one-third of GP consultations relate to psychosocial problems that are often associated with a depressive illness. In the UK, more than 70 million working days are lost yearly, accounting for 17 per cent of all sick leave. 46
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The overall volume of antidepressant use in the UK has been increasing in recent years. This may reflect a number of factors, including increases in the prevalence of depressive disorders, improved detection and management and inappropriate prescribing. TCAs have been available for many years and used to represent the most commonly prescribed class of antidepressant. However, prescribing practices have been changing rapidly since the availability of the SSRIs in the late 1980s. In primary care the vast majority of prescriptions for antidepressants in the treatment www.escriber.com
Depression
Starting treatment • address concerns regarding craving and tolerance • inform of potential side-effects/discontinuation symptoms and of delay between start of treatment and effect Monitoring risk • monitor after 2 weeks of commencing therapy (1 week if
