3.3.2.2 Antidepressants

Uses and targets

Antidepressants also treat anxiety disorders, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD) and some pain syndromes.

• Reuptake transporters clear released monoamines from the synapse: the serotonin transporter (SERT), the noradrenaline transporter (NET) and the dopamine transporter (DAT).

• Blocking a transporter raises extracellular transmitter, but neuronal firing, transporter distribution and autoreceptors shape the result.

• Prefrontal dopamine rises when NET is blocked, because the prefrontal cortex has few dopamine transporters and relies on NET to clear dopamine. SSRIs leave prefrontal dopamine largely unchanged.

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SNRIs are defined by inhibiting both SERT and NET, which sets them apart from SSRIs, tricyclics, monoamine oxidase inhibitors (MAOIs) and alpha-2 antagonists.

SSRIs

• Escitalopram is the isolated S-enantiomer of racemic citalopram.

• Fluvoxamine's sigma-1 agonism is linked to anxiolytic effects and possible benefit in psychotic depression.

• Fluvoxamine's CYP1A2 inhibition raises levels of clozapine, olanzapine, theophylline and caffeine several-fold.

• Fluoxetine, paroxetine and fluvoxamine have substantial CYP interactions, while sertraline, citalopram and escitalopram have fewer.

• Norfluoxetine, fluoxetine's active metabolite, has a half-life of one to two weeks, so about five weeks must pass after fluoxetine before an MAOI is started.

• Sertraline is preferred after myocardial infarction: the SADHART trial supports its safety after acute coronary syndromes, and it has few interactions and little effect on the corrected QT interval (QTc).

• In breast-feeding, fluoxetine gives the greatest milk transfer and infant exposure, whereas sertraline and paroxetine give very low exposure.

• Premature ejaculation responds to fluoxetine or sertraline, because SSRIs raise the ejaculatory threshold.

SNRIs, reboxetine and bupropion

• Venlafaxine binds SERT far more strongly than NET, so it acts like an SSRI at low doses and adds noradrenaline reuptake inhibition (and a weak dopamine effect) only at higher doses, above about 150 mg.

• Duloxetine inhibits reuptake of serotonin and noradrenaline and holds UK licences for major depression, generalised anxiety disorder, diabetic peripheral neuropathic pain and stress urinary incontinence.

• Reboxetine blocks NET with little action at serotonin or dopamine transporters or at muscarinic, histamine and alpha-1 receptors.

  • It is the antidepressant most likely to cause insomnia, being activating without any sedating receptor blockade.

  • Its apparently anticholinergic effects (urinary hesitancy, sweating, tachycardia) are noradrenergic, so an alpha-1 antagonist relieves the hesitancy.

• Bupropion inhibits noradrenaline and dopamine reuptake with no meaningful serotonergic action, and much of its effect probably comes from its brain metabolite hydroxybupropion.

  • It is a non-competitive antagonist at nicotinic acetylcholine receptors, which is thought to help smoking cessation; nicotine and varenicline are nicotinic agonists.

  • It lowers the seizure threshold in proportion to dose and peak level, worst with immediate-release tablets, so it is contraindicated where seizures are a risk.

Receptor-acting antidepressants

Mirtazapine raises monoamine release by alpha-2 antagonism, not by reuptake or monoamine oxidase (MAO) inhibition.

Mirtazapine and mianserin

• Sedation at low doses comes from H1 blockade, one of the most potent in psychiatric use.

• At higher doses, alpha-2 antagonism raises noradrenergic tone and offsets the H1 sedation, so drowsiness is often less marked.

• 5-HT3 antagonism explains mirtazapine's low rate of nausea and gastrointestinal upset.

• Mirtazapine causes relatively little sexual dysfunction, because it raises serotonin release while blocking 5-HT2 receptors, with no SERT blockade.

• Mirtazapine can suppress marrow, usually as neutropenia and rarely as agranulocytosis, so signs of infection call for an urgent white cell count.

• Mianserin carries a risk of blood dyscrasias and needs a full blood count every four weeks for the first three months.

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Trazodone

• Trazodone is the antidepressant most linked to priapism, because its alpha-1 blockade prevents sympathetically driven detumescence.

• H1 and 5-HT2A blockade make it sedating, so it is taken at night; antidepressant doses are higher than sedating doses.

• It can prolong the QTc at ordinary therapeutic doses through blockade of the hERG (human ether-a-go-go-related gene) potassium channel.

Vortioxetine and agomelatine

• Nausea is very common with vortioxetine.

• Agomelatine improves disturbed sleep-wake cycles by melatonin receptor agonism at the suprachiasmatic nucleus, resetting the circadian clock rather than sedating.

• Agomelatine causes sexual dysfunction at close to placebo rate, so it is a recognised switch when an SSRI has impaired sexual function; its withdrawal burden is also low.

• Agomelatine is hepatotoxic: check liver tests at baseline and at about 3, 6, 12 and 24 weeks, and stop if transaminases exceed three times the upper limit of normal.

Monoamine oxidase inhibitors

The enzymes

Mitochondrial MAO breaks down monoamines in neurons, gut and liver.

• Phenelzine and tranylcypromine inhibit both isoforms irreversibly, so recovery needs new enzyme over roughly two weeks.

• Moclobemide is a selective, reversible, competitive inhibitor of MAO-A (RIMA). Tyramine can displace it, so dietary restriction is milder than with irreversible MAOIs, though interaction precautions remain.

• Selegiline inhibits MAO irreversibly and is selective for MAO-B at low oral doses. An antidepressant effect needs higher doses or the transdermal route, which also inhibits brain MAO-A.

The cheese reaction

• Barry Blackwell is credited with first describing the cheese reaction, the tyramine-induced hypertensive crisis on MAOIs.

• MAO-A in the gut wall and liver normally destroys dietary tyramine, and an irreversible MAOI removes that barrier.

• Tyramine is an indirect sympathomimetic: it enters the sympathetic nerve terminal through NET, the transporter tricyclics block, and releases stored noradrenaline.

• The crisis presents with sudden occipital headache, palpitations and neck stiffness, and the danger is intracranial haemorrhage.

• This food-triggered risk is specific to MAOIs.

• Patients avoid foods made rich in tyramine by ageing, fermentation, curing, pickling or protein breakdown: aged cheese, cured meat, soy sauce, yeast extracts.

• Fresh, unfermented foods carry only trace tyramine.

• Irreversible non-selective MAOIs are contraindicated in phaeochromocytoma, because they block breakdown of the tumour's catecholamines.

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Interactions

• Serotonin toxicity with a second antidepressant follows the partner's serotonin reuptake inhibition, so SSRIs and venlafaxine are contraindicated with an MAOI.

• Only a weakly serotonergic tricyclic such as trimipramine or amitriptyline is a comparatively safe partner.

• Washout is usually two weeks after stopping an irreversible MAOI.

• Linezolid is a weak reversible MAO inhibitor, so adding it to sertraline can cause serotonin syndrome within a day: agitation, sweating, fever, tremor, hyperreflexia, and clonus most marked in the legs.

Uses and adverse effects

• Atypical depression responds better to MAOIs, phenelzine above all, than to tricyclics.

• Phenelzine has its best-replicated anxiolytic evidence in social anxiety disorder, with about two-thirds responding acutely.

• Common MAOI adverse effects are insomnia, postural hypotension, oedema and sexual dysfunction, while organ-toxic reactions are rare.

Tricyclic antidepressants

Secondary amines tend to be more noradrenergic, and tertiary amines more sedating and more antimuscarinic.

• Tricyclic sedation comes from H1 blockade, not muscarinic blockade, and postural hypotension from alpha-1 blockade, not muscarinic, H1 or beta action.

• Tricyclic adverse effects are receptor-driven; endocrine and renal effects belong to lithium, not tricyclics.

• Angle-closure glaucoma can be precipitated or worsened by antimuscarinic antidepressants, with risk following antimuscarinic potency: strongest with tertiary-amine tricyclics, and paroxetine also needs caution.

Differences between tricyclics

• The fatal toxicity index is overdose deaths relative to prescriptions; dosulepin's is highest through cardiac sodium channel blockade.

• Lofepramine is the usual tricyclic for older or medically frail patients, or when a tricyclic is wanted but overdose is a worry.

Cardiotoxicity and overdose

• Fast sodium channel blockade is the main mechanism: it slows phase 0 depolarisation and widens the QRS and PR intervals, with a terminal R wave in lead aVR.

• hERG potassium channel blockade lengthens the QT instead, and is a separate effect.

• Ventricular arrhythmia, not seizures, is the principal cause of death in tricyclic overdose.

• Class Ia antiarrhythmics such as quinidine and procainamide share the sodium channel blockade and worsen it, while sodium loading and alkalinisation counteract it.

• A tricyclic that causes an arrhythmia at therapeutic dose is withdrawn at once, not reduced or continued pending review.

Withdrawal

Sudden withdrawal of a long-term tricyclic causes cholinergic rebound, with parasympathetic symptoms within days, after prolonged muscarinic blockade and receptor adaptation.

From transporter to mood

• Serotonin rises quickly after SERT blockade, but raphe 5-HT1A and terminal 5-HT1B autoreceptors at first limit firing and release.

• Autoreceptors adapt over several weeks, which may allow greater transmission; pindolol augmentation tested this model, which does not explain all response.

• Ketamine shows that improvement can come rapidly through other pathways.

• Early anxiety and agitation on starting an SSRI are attributed to acute stimulation of postsynaptic 5-HT2 receptors in limbic cortex.

• Chronic tricyclic treatment for two to four weeks, not a single dose, down-regulates postsynaptic beta-adrenergic receptors.

• Tri-iodothyronine (T3), used for augmentation, acts through nuclear receptors that are themselves transcription factors, so it changes gene transcription directly, unlike drugs acting at membrane receptors, transporters or enzymes.

• The neurotrophic hypothesis holds that stress reduces plasticity and that treatment may reverse this through pathways including brain-derived neurotrophic factor; rodent evidence supports it more than human findings.

• A single antidepressant dose reduces the amygdala's response to fearful faces, and the cognitive neuropsychological model proposes that mood improves later through repeated experience.

• SSRI efficacy does not prove that serotonin deficiency causes depression, and depletion and metabolite studies do not support a simple deficiency model.

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Discontinuation syndrome

• Abrupt cessation of an SSRI after weeks of treatment produces symptoms within days, about three to five half-lives: dizziness, electric-shock sensations, sleep disturbance, vivid dreams, nausea and irritability.

• Symptoms settle within hours of restarting the drug.

• Risk is highest with a short half-life and no active metabolite (paroxetine, venlafaxine), while fluoxetine tapers itself.

• Paroxetine also inhibits its own metabolism through CYP2D6, so its level falls steeply on stopping.

• Venlafaxine produces the most severe syndrome, often in waves, because its half-life is about five hours and its metabolite's about eleven.

Adverse effects compared across drugs

Hyponatraemia

• SSRIs are most strongly linked to the syndrome of inappropriate antidiuretic hormone secretion (SIADH), because serotonin reuptake inhibition drives antidiuretic hormone excess.

• Risk is much lower with mirtazapine, and tricyclics carry less risk than SSRIs, SNRIs and trazodone.

• Hyponatraemia usually develops within about 30 days of starting.

• Risk factors are older age, female sex, low body weight, low baseline sodium, warm weather and reduced renal function.

• Sodium-lowering co-prescriptions add risk: thiazides and other diuretics, non-steroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, calcium channel blockers and carbamazepine.

• It presents with cramps, headache, lethargy, confusion, falls and seizures, from water retention and cerebral swelling.

• Gradual confusion or non-specific decline in an older person soon after starting an SSRI, with normal observations, calls for urea and electrolytes.

• The next antidepressant should act mainly on noradrenaline (for example lofepramine) or inhibit MAO-A.

Sexual function and weight

Sexual dysfunction follows serotonin reuptake inhibition.

• Mirtazapine's weight gain comes from potent H1 antagonism with a contribution from 5-HT2C antagonism; agomelatine shares the 5-HT2C antagonism but is weight neutral.

• Bupropion causes modest weight loss sustained over long-term treatment, and causes no sedation, anticholinergic effects or sexual dysfunction.

• Reboxetine can still cause sexual effects.

Sleep

H1, alpha-1 or 5-HT2A antagonism sedates and melatonergic agonism promotes sleep, while purely noradrenergic reuptake inhibition activates.

Bleeding and the QTc

• SSRIs raise the risk of gastrointestinal bleeding, most in older people, because blocking the platelet SERT empties platelet serotonin stores and weakens aggregation.

• This adds to warfarin and other drugs that raise bleeding risk.

• Citalopram prolongs the QTc in a dose-related way, so the Medicines and Healthcare products Regulatory Agency limits it to 20 mg daily over 65.

• Escitalopram also prolongs the QTc dose-dependently.

• Mirtazapine, sertraline and reboxetine sit at the low-risk end for QTc.

Blood pressure and sweating

• Sustained hypertension is a dose-related SNRI effect of noradrenaline reuptake inhibition, so blood pressure is monitored on venlafaxine.

• SSRIs can cause movement disorders and raised prolactin, but not sustained hypertension.

• Postural hypotension follows alpha-1 blockade and MAOI autonomic effects: lowest with SSRIs and SNRIs, more with tricyclics, MAOIs, trazodone and mirtazapine.

• Noradrenergic antidepressants cause dose-related excessive sweating, which alpha-1 blockers such as terazosin, beta-blockers or anticholinergics can reduce.

Manic switch in bipolar depression

Treatment is chosen on prior response, tolerability, interactions and overdose risk.