The main types of antidepressants are:
- Selective serotonin reuptake inhibitors (SSRIs)
- Serotonin and norepinephrine reuptake inhibitors (SNRIs)
- Tricyclic antidepressants (TCAs)
- Others (e.g., mirtazapine and vortioxetine)
Mechanism of Action
Neurones (nerve cells) communicate with each other at connections called synapses. Each neurone is connected to many other neurones via synapses. The synapse is found at the end of one neurone (the axon terminal) and the start of another (the dendrite). The axon terminal releases chemicals called neurotransmitters, such as dopamine, serotonin, noradrenaline and gamma-aminobutyric acid (GABA). The neurotransmitter crosses the synapse and stimulates receptors on the post-synaptic membrane, creating a response in the neurone. Once this stimulation occurs, the neurotransmitter is returned to the axon terminal of the original neurone (reuptake).
Selective serotonin reuptake inhibitors (SSRIs) work by blocking the reuptake of serotonin by the presynaptic membrane on the axon terminal. This results in more serotonin in the synapses throughout the central nervous system, boosting the communication between neurones.
Serotonin and norepinephrine reuptake inhibitors (SNRIs) work by blocking the reuptake of serotonin and noradrenaline by the presynaptic membrane. This results in more serotonin and noradrenaline in the synapses throughout the central nervous system.
Tricyclic antidepressants have a more complex mechanism. They block the reuptake of serotonin and noradrenaline by the presynaptic membrane. They also have additional actions, including blocking acetylcholine and histamine receptors, which give them anticholinergic and sedative side effects.
Selective Serotonin Reuptake Inhibitors
Examples of SSRIs include sertraline, citalopram, escitalopram, fluoxetine and paroxetine.
Sertraline tends to have helpful anti-anxiety effects and is considered to be one of the safest in patients with heart disease (e.g., following myocardial infarction or heart failure). However, it is associated with a higher rate of diarrhoea.
Citalopram can prolong the QT interval, although this effect is dose-dependent (a higher dose is more likely to cause a prolonged QT). QT prolongation can lead to torsades de pointes. Along with escitalopram, it is considered to be the least safe SSRI in patients with heart disease and arrhythmia (although still a lot safer than TCAs).
Fluoxetine has a particularly long half-life of around 4-7 days. This means it remains active in the body long after stopping. It is the usual first-line choice in children and adolescents.
Paroxetine may cause weight gain and is more likely to cause discontinuation symptoms.
Key side effects of SSRIs include:
- Gastrointestinal symptoms (e.g., nausea and diarrhoea)
- Headaches
- Sexual dysfunction, such as loss of libido, erectile dysfunction and difficulty achieving an organism
- Hyponatraemia (due to SIADH)
- Anxiety or agitation, typically in the first few weeks of use
- Increased suicidal thoughts, suicide risk and self-harm (this applies to all antidepressants)
- Increased risk of bleeding (e.g., gastrointestinal bleeding, intracranial haemorrhage and postpartum haemorrhage)
The risk of bleeding is significantly increased when SSRIs are taken alongside anticoagulants or NSAIDs.
Serotonin and Norepinephrine Reuptake Inhibitors
Examples of SNRIs include duloxetine and venlafaxine. They have similar side effects to SSRIs. They can increase the blood pressure and are contraindicated in uncontrolled hypertension.
Venlafaxine is often used when there is an inadequate response to other antidepressants. It is more likely to cause discontinuation symptoms when stopped. It has an increased risk of death from overdose.
Duloxetine is also used to treat neuropathic pain, particularly diabetic neuropathy.
Tricyclic Antidepressants
Examples of tricyclic antidepressants (TCAs) include amitriptyline and nortriptyline. They are commonly used at a low dose to treat neuropathic pain. The neuropathic pain dose is too low to treat depression.
Tricyclic antidepressants are particularly known to cause arrhythmias, including tachycardia, prolonged QT interval and bundle branch block. The effects are dose-dependent. Their effect on the heart makes them very dangerous in overdose, with a high risk of death. For these reasons, they are not generally used to treat depression, especially in patients with heart disease or risk factors for suicide.
They have anticholinergic side effects, such as dry mouth, constipation, urinary retention, blurred vision and cognitive impairment. They also cause sedation and are typically taken at night.
Other Antidepressants
Mirtazapine has key side effects of sedation, increased appetite and weight gain. It is taken at night due to the sedative effect. The sedative effect appears to be greatest at low doses (e.g., 15mg) and less present at higher doses (e.g., 45mg). Mirtazapine is less likely to cause sexual dysfunction compared with SSRIs.
TOM TIP: The side effects of sedation and increased appetite may be beneficial, depending on the patient. In someone with a loss of appetite, weight loss, and poor sleep due to depression, these side effects can be very helpful. For this reason, it is commonly used in older patients. However, in someone else who is overweight and oversleeping already, these side effects would be a big problem.
Vortioxetine is used as a third-line treatment after an inadequate response to two other antidepressants (NICE TA367 2015). It acts as a serotonin reuptake inhibitor and also acts to stimulate and block various types of serotonin receptors. It has helpful anti-anxiety effects. It has a particularly good side effect profile and is considered safe with heart disease. It has minimal effect on sexual function and almost no risk of discontinuation symptoms. However, it commonly causes nausea for the first few weeks.
Starting Antidepressants
When starting antidepressants, there can be an initial period of worsened agitation, anxiety, suicidal thoughts and acts of suicide. This is particularly a problem in younger patients.
The NICE clinical knowledge summaries (2024) recommend arranging a review within two weeks of starting an antidepressant (one week in patients aged 18-25 due to the increased risk of suicide).
There is usually a noticeable response within 2-4 weeks of treatment. Where there is an inadequate response, the next step is to consider increasing the dose or switching to an alternative treatment.
Swapping Antidepressants
Swapping antidepressants depends on the medication involved. Always check the guidelines to ensure the correct regime for swapping.
Some can be directly switched, stopping the previous medication and starting the new one the next day. This is the case for switching between SSRIs and SNRIs (except fluoxetine due to the long half-life).
Others need to be cross-tapered over several weeks (e.g., switching between an SSRI and mirtazapine), gradually reducing the dose of the existing drug while increasing the dose of the new one.
Stopping Antidepressants
Once antidepressants are started, they should be continued for at least six months before stopping (or two years in recurrent depression). Withdrawing them too early can lead to the depression returning.
Antidepressants should not be stopped suddenly. The dose should be reduced slowly over at least four weeks to minimise discontinuation symptoms (unless there is an urgent need to stop).
Discontinuation symptoms are usually mild but occasionally are more severe. They typically start within 2-3 days of stopping treatment and resolve within 1-2 weeks. Possible symptoms include:
- Flu-like symptoms
- Electric shock-like sensations
- Irritability
- Insomnia
- Vivid dreams
Serotonin Syndrome
Serotonin syndrome can range from mild symptoms to severe and potentially life-threatening. It is caused by excessive serotonin activity. It usually occurs with higher doses of antidepressants and when multiple antidepressants are used together.
There is a long list of possible symptoms, which fall into three categories:
- Altered mental state (e.g., anxiety and agitation)
- Autonomic nervous system hyperactivity (e.g., tachycardia, hypertension and hyperthermia)
- Neuromuscular hyperactivity (e.g., hyperreflexia, tremor and rigidity)
Severe serotonin syndrome is a medical emergency. Severe cases can cause confusion, seizures, severe hyperthermia (over 40°C) and respiratory failure.
Diagnosis is based on the clinical presentation and excluding other causes of the symptoms. Management involves supportive care (e.g., sedation with benzodiazepines) and withdrawal of the causative medications.
Last updated June 2024
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