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Antidepressant drugs

Last updated on November 17th, 2021

Antidepressant drugs are effective for treating moderate to severe depression associated with psychomotor and physiological changes such as loss of appetite and sleep disturbance; improvement in sleep is usually the first benefit of therapy. They are also effective for dysthymia (lower grade chronic depression). Antidepressant drugs are not generally effective in mild depression, and cognitive behavioural therapy should be considered initially; however, a trial of antidepressant therapy may be considered in cases refractory to psychological treatments or those associated with psychosocial or medical problems. Drug treatment of mild depression may also be considered in patients with a history of moderate or severe depression.


The major classes of antidepressant drugs include the tricyclics and related antidepressants, the selective serotonin re-uptake inhibitors (SSRIs), and the monoamine oxidase inhibitors (MAOIs). A number of antidepressant drugs cannot be accommodated easily into this classification.

There is little to choose between the different classes of antidepressant drugs in terms of efficacy, so choice should be based on the individual patient’s requirements, including the presence of concomitant disease, existing therapy, suicide risk, and previous response to antidepressant therapy. Since there may be an interval of 2 weeks before the antidepressant action takes place, electroconvulsive treatment may be required in severe depression when delay is hazardous or intolerable.

SSRIs are better tolerated and are safer in overdose than other classes of antidepressants and should be considered first-line for treating depression. In patients with unstable angina or who have had a recent myocardial infarction, sertraline has been shown to be safe.

Tricyclic antidepressants have similar efficacy to SSRIs but are more likely to be discontinued because of side-effects; toxicity in overdosage is also a problem.

MAOIs have dangerous interactions with some foods and drugs, and should be reserved for use by specialists.

Although anxiety is often present in depressive illness (and may be the presenting symptom), the use of an antipsychotic or an anxiolytic may mask the true diagnosis. Anxiolytics or antipsychotic drugs should therefore be used with caution in depression but they are useful adjuncts in agitated patients.


Hyponatraemia and antidepressant therapy

Hyponatraemia (usually in the elderly and possibly due to inappropriate secretion of antidiuretic hormone) has been associated with all types of antidepressants; however, it has been reported more frequently with SSRIs than with other antidepressants. The CSM has advised that hyponatraemia should be considered in all patients who develop drowsiness, confusion, or convulsions while taking an antidepressant.

St John’s wort (Hypericum perforatum) is a popular herbal remedy on sale to the public for treating mild depression. However, preparations of St John’s wort can induce drug metabolising enzymes and a number of important interactions with conventional drugs have been identified. The amount of active ingredient can vary between different preparations of St John’s wort and switching from one to another can change the degree of enzyme induction. Furthermore, when a patient stops taking St John’s wort, concentrations of interacting drugs may increase, leading to toxicity. Antidepressant drugs should not be used with St John’s wort because of the potential for interaction.

Suicidal behaviour and antidepressant therapy

The use of antidepressants has been linked with suicidal thoughts and behaviour; children, young adults, and patients with a history of suicidal behaviour are particularly at risk. Where necessary patients should be monitored for suicidal behaviour, self-harm, or hostility, particularly at the beginning of treatment or if the dose is changed.


Patients should be reviewed every 1-2 weeks at the start of antidepressant treatment. Treatment should be continued for at least 4 weeks (6 weeks in the elderly) before considering whether to switch antidepressant due to lack of efficacy. In cases of partial response, continue for a further 2 weeks (elderly patients may take longer to respond).

Following remission, antidepressant treatment should be continued at the same dose for at least 6 months (about 12 months in the elderly). Patients with a history of recurrent depression should continue to receive maintenance treatment for at least 2 years.

Failure to respond

Failure to respond to initial treatment with an SSRI may require an increase in the dose, or switching to a different SSRI or mirtazapine; in patients with atypical depression, an MAOI such as phenelzine may be effective. Other second-line choices include lofepramine, moclobemide, and reboxetine. Other tricyclic antidepressants and venlafaxine should be considered for more severe forms of depression; dosulepin (dothiepin) and irreversible MAOIs should only be prescribed by specialists.

Failure to respond to a second antidepressant may require the addition of another antidepressant of a different class, or an augmenting agent such as lithium, but such adjunctive treatment should be initiated only by doctors with special experience of these combinations. Electro-convulsive therapy may be initiated in severe refractory depression.


Gastro-intestinal symptoms of nausea, vomiting, and anorexia, accompanied by headache, giddiness, ‘chills’, and insomnia, and sometimes by hypomania, panic-anxiety, and extreme motor restlessness may occur if an antidepressant (particularly an MAOI) is stopped suddenly after regular administration for 8 weeks or more. The dose should preferably be reduced gradually over about 4 weeks, or longer if withdrawal symptoms emerge (6 months in patients who have been on long-term maintenance treatment). SSRIs have been associated with a specific withdrawal syndrome.

Anxiety disorders and obsessive-compulsive disorder

Management of acute anxiety generally involves the use of a benzodiazepine or buspirone. For chronic anxiety (of longer than 4 weeks’ duration) it may be appropriate to use an antidepressant. Combined therapy with a benzodiazepine may be required until the antidepressant takes effect. Generalised anxiety disorder, a form of chronic anxiety, is treated with an SSRI such as escitalopram or paroxetine; pregabalin and venlafaxine are also licensed for the treatment of generalised anxiety disorder.

Panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and phobic states such as social anxiety disorder are treated with SSRIs. Clomipramine or imipramine can be used second-line in panic disorder [unlicensed]; clomipramine can also be used second-line for obsessive-compulsive disorder. Moclobemide is licensed for the treatment of social anxiety disorder.


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