In patients with moderate to severe depression routine antidepressant therapy is effective (as highlighted by Cipriani et al. (2018) following meta-analysis of results from clinical trials of 21 different antidepressants)- and is recommended to be combined with psychological therapy. Drug treatment of mild depression may also be considered in patients with a history of moderate or severe depression. Improvement in sleep is usually the first benefit of antidepressant therapy, with additional beneficial effects on psychomotor and physiological changes such as loss of appetite. The information provided in this section summarises the classes of antidepressants available to the prescriber. For a more critical review of antidepressant therapy see our topic Depression within in the Psychiatric disease module.
The major classes of antidepressant drugs include the tricyclic and related antidepressants, selective serotonin re-uptake inhibitors (SSRIs), the selective serotonin and norepinephrine re-uptake inhibitors (SNRIs) and the monoamine oxidase inhibitors (MAOIs). A small number of drugs don’t easily fall into this classification and are listed under Atypical antidepressants below.
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 other existing disease and therapy, suicide risk, and previous response to antidepressant therapy.
SSRIs are better tolerated and are safer in overdose than other classes of antidepressants and should be considered first-line for treating depression. Notably, sertraline has been shown to be safe in patients who have had a recent myocardial infarction or who have unstable angina. TCAs have similar efficacy to SSRIs, but their more troublesome side-effects leads to patients being more likely to discontinue treatment. TCAs are also more toxic in overdose than SSRIs. MAOIs have dangerous interactions with some foods and drugs, and should be reserved for use by specialists.
Anxiolytics or antipsychotic drugs should be used with caution in depression which often presents as anxiety, as they can mask the true diagnosis, but are useful adjuncts in agitated patients.
Selective serotonin re-uptake inhibitors (SSRIs)
SSRIs are the most commonly prescribed class of antidepressants. They are highly effective and generally well tolerated compared to other types of antidepressants. Side effects of SSRIs may include nausea, vomiting, diarrhoea, sexual dysfunction, headache, weight gain, anxiety, dizziness, dry mouth, and insomnia. Caution should be used when prescribing SSRIs alongside other drugs that increase the risk of bleeding. SSRIs should not be used in patients with poorly controlled epilepsy or in patients entering manic phase. Common shared side-effects (often dose-related) include abdominal pain, constipation, diarrhoea, dyspepsia, nausea and vomiting. An uncommon, but potentially serious side-effect is serotonin syndrome.
Citalopram- used to manage depressive illness and panic disorder.
Escitalopram (the active enantiomer of citalopram)- used to manage depressive illness, generalised anxiety disorder, obsessive-compulsive disorder, panic disorder and social anxiety disorder.
Paroxetine- used to manage major depression, social anxiety disorder, post-traumatic stress disorder (PTSD), generalised anxiety disorder, obsessive-compulsive disorder and panic disorder
Fluoxetine (Prozac)- used to treat major depression, bulimia nervosa and obsessive-compulsive disorder. Prescribers should consider the long half-life of when adjusting dosage, especially in regards to overdosage.
Fluvoxamine- used to manage depressive illness and obsessive-compulsive disorder.
Sertraline- used to manage depressive illness, obsessive-compulsive disorder, panic disorder, social anxiety disorder and PTSD.
Failure to respond to initial treatment with an SSRI may require an increase in the dose, or switching to a different SSRI or mirtazapine. Other second-line choices include lofepramine, moclobemide, and reboxetine.
Selective serotonin and norepinephrine re-uptake inhibitors (SNRIs)
None of these drugs should be prescribed within 14 days of an MAOI and at least 7 days should be allowed between stopping their use and administering a MAOI.
Desvenlafaxine (not UK)- indicated for major depressive disorder.
Duloxetine- used to manage major depressive disorder, generalised anxiety disorder, diabetic neuropathy and moderate to severe stress urinary incontinence. Use caution when prescribing alongside drugs that increase risk of bleeding.
Venlafaxine- indicated for major depression, generalised anxiety disorder and social anxiety disorder. Contra-indicated in patients with conditions associated with high risk of cardiac arrhythmia or uncontrolled hypertension.
Milnacipran (not UK)- used to treat the chronic pain caused by fibromyalgia, not used to treat depression.
Levomilnacipran (not UK)- used to treat major depressive disorder.
Most common side-effects of SNRIs are nausea, dizziness, and sweating. Other side-effects include tiredness, constipation, insomnia, anxiety, headache, and loss of appetite.
Duloxetine and milnacipran should not be used in patients with uncontrolled narrow angle or angle-closure glaucoma.
Tricyclic antidepressants (TCAs) and related antidepressants
TCAs share a similar chemical structure and biological effects. TCAs block the re-uptake of both serotonin and noradrenaline, although to different extents. For example, clomipramine is more selective for serotonin re-uptake, and reboxetine and lofepramine are somewhat more selective for noradrenaline re-uptake. Other TCAs such as nortriptyline, show no such selectivity. Evidence indicates that the secondary amine tricyclic antidepressants, including desipramine HCl, may have greater activity in blocking the re-uptake of norepinephrine. Tertiary amine tricyclic antidepressants, such as amitriptyline, may have greater effect on serotonin re-uptake. Additionally, TCAs block muscarinic M1, histamine H1, and alpha-adrenoceptors. Tricyclic and related antidepressant drugs can be roughly divided into those with additional sedative properties (amitriptyline, clomipramine, dosulepin, doxepin, mianserin, trazodone, and trimipramine) and those that are less sedating (imipramine, lofepramine, and nortriptyline). Agitated and anxious patients tend to respond best to the sedative compounds, whereas withdrawn and apathetic patients will often obtain most benefit from the less sedating ones.
TCAs are approved for treating several types of depression, obsessive compulsive disorder, and bedwetting (nocturnal enuresis). Also used for several off-label conditions such as panic disorder, bulimia, chronic pain (for example, migraine, tension headaches, diabetic neuropathy, and post herpetic neuralgia), phantom limb pain, chronic itching, and premenstrual symptoms
Although effective, TCAs have largely been replaced by newer antidepressants that generally cause fewer side-effects.
Amitriptyline - not recommended for depressive illness because of its toxicity in overdosage- used for migraine prophylaxis, neuropathic pain, abdominal pain or discomfort (in patients who have not responded to laxatives, loperamide, or antispasmodics)
Doxepin- used for depressive illness (especially where sedation is required) and pruritus of eczema (topical application). This TCA acts as a selective noradrenaline reuptake inhibitor. Dizziness and drowsiness are very common side-effects, as are agitation, anxiety, confusion, irritability, paraesthesia and sleep disturbance.
Lofepramine- used to treat depressive illness. Common side-effects include dizziness, agitation, anxiety, confusion, irritability, paraesthesia, postural hypotension and sleep disturbance
Dosulepin hydrochloride- used for depressive illness (especially where sedation is required). Common side-effects include dizziness, agitation, anxiety, confusion, irritability, paraesthesia, postural hypotension and sleep disturbance
Desipramine hydrochloride (not UK), is approved in the US to treat symptoms of depression. Use of desipramine in patients being treated with MAOI antidepressants (e.g. linezolid) is contraindicated because of an increased risk of serotonin syndrome. Desipramine may cause exacerbation of psychosis in schizophrenic patients. Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug.
Imipramine hydrochloride – used for depressive illness and nocturnal enuresis. Common side-effects include fatigue, flushing, headache, palpitations and restlessness.
Nortriptyline – prescribed for depressive illness and neuropathic pain. Treatment should be stopped if the patient enters a manic phase. Common side-effects include fatigue, hypertension, mydriasis and restlessness
Amoxapine (not UK)- used to treat symptoms of depression, anxiety, or agitation. Do not use this medicine within 14 days of taking an MAOI antidepressant.
Clomipramine hydrochloride- prescribed for depressive illness, phobic and obsessional states and as an adjunctive treatment of cataplexy associated with narcolepsy. Common side-effects include abdominal pain, aggression, diarrhoea, fatigue, flushing, hypertension, impaired memory, muscle hypertonia, muscle weakness, mydriasis, myoclonus, restlessness and yawning.
Maprotiline (not UK)- used to treat major depressive disorder, depressive neurosis, and manic-depression illness. Avoid alcohol as it can increase some of the side-effects of maprotiline. Maprotiline can impair thinking or reactions, so patients are recommended to avoid activities that require alertness (e.g. driving)
Trimipramine- used to treat depressive illness (particularly where sedation is required). Side-effects can include agitation, anorexia, anxiety, arrhythmia, blurred vision, confusion, constipation, dizziness and dry mouth. Trimipramine is also a serotonin 5-HT2 receptor antagonist.
Protriptyline (not UK)- used to treat symptoms of depression. Do not use this medicine within 14 days of taking an MAOI antidepressant. Common side-effects can include nausea, vomiting, loss of appetite, anxiety, insomnia, dry mouth, little or no urinating and constipation.
Monoamine oxidase inhibitor antidepressants (MAOIs)
MAOIs block the activity of monoamine oxidase, an enzyme that breaks down norepinephrine, serotonin, and dopamine in the brain and other parts of the body. MAOIs are used much less frequently than tricyclic and related antidepressants, or SSRIs and related antidepressants because of the dangers of dietary and drug interactions. MAOIs exhibit some benefit for phobic patients and depressed patients with atypical, hypochondriacal, or hysterical features, but should only be prescribed by specialists. In general, MAOIs have been replaced by newer antidepressants that are safer and cause fewer side-effects. Common side-effects include postural hypotension, weight gain, and sexual side effects.
Rasagiline and selegiline are irreversible MAOB inhibitors used not to treat depression, but to treat Parkinson's disease as a monotherapy or as an adjunct to co-beneldopa or co-careldopa to manage 'end-of-dose' fluctuations.
Each drug in this category has a unique molecular mechanism of action, or a chemical structure that excludes them from the classification above. However, like other antidepressants, atypical antidepressants affect the levels or effects of dopamine, serotonin, and norepinephrine in the brain.
Bupropion- used to aid smoking cessation in combination with motivational support in nicotine-dependent patients. This drug should not be used in patients with seizure disorders, eating disorders, and within 2 weeks of using MAOI. It generally does not cause weight gain or sexual problems.
Mirtazapine- a presynaptic α2-adrenoceptor and serotonin 5-HT2 receptor antagonist which increases central noradrenergic and serotonergic neurotransmission. Used to manage major depression.
Nefazodone (not UK)- a serotonin 5-HT2 receptor antagonist also inhibiting serotonin and norepinephrine re-uptake. Used to manage depression, including major depressive disorder. Nefazodone should not be prescribed to patients with active liver disease.
Trazodone- principally a serotonin 5-HT2 receptor antagonist, used to manage depressive illness, particularly where sedation is required.
Vilazodone (not UK)- a potent serotonin 5-HT1A receptor partial agonist, with combined inhibitory action against serotonin re-uptake. Used to manage major depressive disorder. Vilazodone is not associated with significant weight gain or sexual dysfunction.
Vortioxetine (not UK)- a partial agonist of 5-HT1A and 5-HT1B receptors and antagonist of the 5-HT7 receptor used to manage major depressive disorder. May also inhibit re-uptake of serotonin.
Side-effect profiles are as unique as their mechanisms of action. Some common side effects include dry mouth, constipation, dizziness, and light headedness. Mirtazapine and trazodone cause drowsiness and are usually taken at bedtime
Note: The drug lists presented here are not exhaustive, but are intended to represent the majority of antidepressants in use in the UK and US. Additional drugs may be approved in other countries.
Antidepressants- an introduction
This 13-slide slide set created with PowerPoint provides an introduction to antidepressants describing their discovery and development; their modes of action and relationship to the monoamine hypothesis of depression; and their efficacy, latency and unwanted actions. The beginner level introduction is tailored to aid the understanding of individual antidepressants. Contributed by Christopher Fowler, Umeå University, Sweden.