Who Benefits From Antidepressants?

Systematic reviews of studies of patients over 16 years old, have shown than all classes of antidepressants improve symptoms in acute treatment of all grades of depression. They are just as effective in the elderly.

Bipolar depression and depression in children and adolescents represent special cases and will be considered under their own headings.

The specification for the National Enhanced Service for the Management of Depression¹ makes the following observations:

• Depression is one of the three leading causes of disability.
• Clinical depression affects up to 5% of the population at any time.
• One in four patients presenting to their GP suffers from depression.
• Depression accounts for at least 3,000 of the 4,000 suicides each year.
• As many as 75% of cases of depression are not recognised nor treated.
• 80% of people diagnosed as having depression are treated entirely within the Primary Care setting.

Most GPs would put the figure for those treated in primary care around 95 to 98%. The figure of 80% is far too low. The secondary care system could not cope with 1 in 5 of all patients who present in General Practice with depression.

The suggestion that 3 cases of depression in every 4 are neither diagnosed nor treated is superficially a gross denunciation of professional incompetence but it begs several questions. What were the criteria for the diagnosis of depression? Do the unrecognised cases tend to represent the mildest end of the spectrum? Should all those undiagnosed cases be receiving treatment? If not, does failure to make the diagnosis matter? Being unhappy and clinical depression are not the same thing. The paper that was cited was funded by the pharmaceutical industry and inserting its title into a PubMed search failed to identify it in a peer reviewed journal.

NICE advises that screening for depression in primary care can include two simple questions:²

• During the last month, have you often been bothered by feeling down, depressed or hopeless?
• During the last month, have you often been bothered by having little interest or pleasure in doing things?

• There is extensive literature on antidepressants but nearly all comes from Secondary Care, whereas the vast majority of mild or moderate cases are managed in Primary Care.
• Psychiatrists see the more severe cases including those who self-harm or fail to respond to treatment at normal doses.³ Hence when assessing the validity of the evidence it is essential to ask, "Is this relevant to my patient in front of me?"
• The placebo response is very high, especially in mild cases but by and large the response to active treatment is 30% higher. Where response appears very rapid it is probably a placebo effect. In most cases, especially the milder ones, spontaneous remission is likely⁴ although drugs may accelerate this. In severe cases, spontaneous remission is less likely and severe depression can be a fatal disease.
• Severe depression needs treatment. Mild depression may not and it is justified to wait.²

The article on depression covers the usual presentation as well as the many devious ways in which depression may present.

Always remember that the patient may have concurrent problems such as a serious physical illness including metastatic carcinoma. There may be abuse of drugs or alcohol. The patient may be the victim of abuse. An underactive thyroid is possible. Some drugs can cause depression. Where depression is secondary the underlying cause should be addressed but antidepressants may still have a role. Depression may occur in 20 to 25% of patients with Parkinson's Disease and dementia. It may go unnoticed and antidepressants certainly help.

Assessment

Mild to moderate depression is characterised by depressive symptoms and some functional impairment. Severe depression has additional agitation or psychomotor retardation with marked somatic symptoms. Patients who have low mood and loss of desire for pleasure (anhedonia) for >2 weeks are most likely to benefit from antidepressants, as are those who show >3 of the following 7 markers of depression (mnemonic "SUICIDE"):

Suicide plans or ideas or self-harm
Unexplained feelings of guilt
Inability to function (eg psychomotor retardation or agitation)
Concentration impaired
Decreased sleep and/or early morning waking
Energy low (fatigue)

Enquire about these features if depression is possible⁵ but treatment may still be required in their absence. Listen to the patient. Possibly prescribe later. Patients are often reluctant to accept that they are depressed. Written information to digest at their leisure is often helpful.There are a number of patient information leaflets (PILs) available including on depression and related subjects. Give them time to consider the possibility and to return later. They usually do and treatment is successful. When they understand their condition, they will return at an earlier stage if the depression recurs.

In mild depression, no treatment may well be the best option and it is justifiable to await spontaneous recovery. Drugs, in particular, may have more adverse than beneficial effects. Explain all this to the patient, leaving an invitation to return if there is no improvement or if there is deterioration. A wise precaution may be to arrange follow up in 2 weeks.² If mild depression does not resolve, drug treatment is indicated.

Cognitive and Behavioural Therapy

• Cognitive therapy and interpersonal psychotherapy are effective alone in mild to moderate cases. They can be used in more severe cases in conjunction with drugs.⁶
• Nondirective counselling and problem solving treatment are probably effective in mild to moderate depression.
• There is limited evidence that exercise may help lift mood in mild depression.⁷ A Cochrane review of exercise to treat anxiety and depression in children and adolescents found the quality of evidence poor.⁸ It may be beneficial in the elderly.⁹ It may be a useful adjunct to drugs in severe depression.¹⁰
• Disease management programmes may be a cost effective intervention that perhaps needs further development.¹¹

Drugs

Psychiatrists suggest that GPs use doses that are too low and too brief in duration. There may be some justification in this but GPs may also be seeing more mild cases whom they are treating effectively or who are giving a placebo response. Patients are often reluctant to take antidepressants as they fear the stigma of mental illness or they fear addiction. It is worth explaining the difference between antidepressants and benzodiazepines.

Which drug?

• Systematic reviews have shown that the various classes of drugs have similar profiles in terms of speed of onset and rate of response but different profiles in terms of side effects. If a drug fails it may be worth trying one from another class.
• The tricyclic antidepressants (TCAs) generally have more side effects than the selective serotonin reuptake inhibitors (SSRIs), especially sedation but this can be advantageous in anxiety and a loading dose at night can help insomnia. The TCAs tend to be rather cheaper. Cardiotoxicity makes them very dangerous in overdose and extreme caution must be exercised if there is risk of self-harm. Care is needed in the elderly and in those with coronary heart disease. As well as dry mouth and constipation, anticholinergic effects can precipitate urinary retention and glaucoma. The SSRIs can heighten anxiety and have a withdrawal syndrome. One RCT and observational studies have shown that abrupt withdrawal can produce dizziness and rhinitis. If it occurs, change to a longer acting product and withdraw gradually. NICE recommends the SSRIs as first line treatment in most cases.²
• The monoamine oxide inhibitors (MAOIs) are used less often in General Practice nowadays because of drug interactions and tyramine in food or drink can induce a severe hypertensive reaction.
• Systematic reviews have found that St John's Wort is effective in mild to moderate cases with side effects no different from usual antidepressants. Patients often like "natural remedies" but they should be reminded that side effects and toxicity, including teratogenesis and drug interactions are as likely with a herbal remedy as with any pharmaceutical product but they have been rather less thoroughly researched. The NICE guidelines on the management of depression² states that "Although there is evidence that St John's wort may be of benefit in mild or moderate depression, healthcare professionals should not prescribe or advise its use by patients because of uncertainty about appropriate doses, variation in the nature of preparations and potential serious interactions with other drugs (including oral contraceptives, anticoagulants and anticonvulsants)." St John's wort is discussed in far more detail in its own article. It is one of the best researched of the herbal remedies yet the level of information about it would fall far short of that required to obtain a product licence.
• A recent review found that none of the many complementary and alternative medicine treatments for depression had good evidence of efficacy.¹²
• One of the problems of poor outcome in treating depression is poor adherence to the treatment. Interventions to improve compliance improve outcome.¹³

Where patients have failed to respond to treatment there are a number of issues that arise. One is the possibility of incorrect diagnosis. Another is inadequate treatment including failure to take the treatment. When a diagnosis of treatment resistant depression is made there are 3 strategies in clinical use.¹⁴ They are optimization of antidepressant dose, augmentation or combination therapies, and switching therapies. However, the optimal strategy has yet to be identified.

Surgery

Stereotactic surgery is rarely used and only in the most refractory of cases. Modern operations are more precise and less destructive than before.

ECT

Electroconvulsive therapy has had bad publicity but much of the argument is emotional rather than scientific and based on old-fashioned methods of administration. It should be reserved for the more extreme cases, especially where medication has failed or the risk of self-harm does not allow time to wait for the drugs to have effect.¹⁵ It is administered under general anaesthetic with muscle relaxation so that physical damage should no longer be a problem. However, amnesia remains. Bilateral ECT is more effective than unilateral but it has greater side-effects.

Depression is likely to be recurrent unless it was precipitated by a specific life crisis. Some people recommend long term treatment with antidepressants¹⁶ as this is shown to reduce the rate of relapse.

The management of bipolar disorders and depression in children and adolescents has been reviewed by NICE.¹⁷

Bipolar Disorders

Patients with bipolar depression generally spend much more time in the depressive than the manic phase. They have a great risk of suicide.¹⁸ A mood stabilising agent such lithium or lamotrigine must be given with the antidepressant to reduce the risk of swings to mania.¹⁹

Children and adolescents

Depression in children and adolescents should not be seen as a continuum of the disease in adults.
Cognitive behavioural therapy²⁰ appears beneficial in children and adolescents with mild to moderate depression. Interpersonal therapy is likely to be effective in adolescents. TCAs are unlikely to be helpful in adolescents and are ineffective or harmful in children. There has been much publicity about the suggestion that SSRIs, especially paroxetine, may cause an increase in suicidal ideas in children and adolescents. The truth is far from clear²¹ but the risk of suicidal behaviour is increased in the first month after starting antidepressants, especially in the first 9 days. It has been suggested that unpublished data is much less reassuring than that which has been published.²² More research is expected soon.

Most authorities would accept that starting antidepressants in children and adolescents should be in the province of secondary care and GPs are unlikely to have adequate experience and expertise in this uncommon field.