As most antidepressants have similar therapeutic efficacy, the decision regarding which drug to select often rests on adverse effect profiles and potential to cause toxicity.
The commonest unwanted effects are those of the antimuscarinic action, i.e. dry mouth (predisposing to tooth decay), blurred vision and difficulty with accommodation, raised intraocular pressure (glaucoma may be precipitated), bladder neck obstruction (may lead to urinary retention in older males).
Patients may also experience: postural hypotension (through inhibition of a-adrenoceptors) which is often a limiting factor in their utility in the elderly, interference with sexual function, weight gain (through blockade of histamine H, receptors), prolongation of the QT interval of the ECG which predisposes to cardiac arrhythmias especially in overdose (use of TCAs after myocardial infarction is contraindicated).
Some TCAs (especially trimipramine and ami-triptyline) are heavily sedating through a combination of antihistaminergic and a-adrenergic blocking actions. This presents special problems to those whose lives involve driving vehicles or performing skilled tasks. In selected patients, sedation may be beneficial, e.g. a severely depressed person who has a disrupted sleep pattern or marked agitation.
It is essential to remember that there is great heterogeneity in adverse effect profiles between TCAs. Imipramine and lofepramine cause relatively little sedation and lofepramine is associated with milder antimuscarinic effects (but is contraindicated in patients with severe liver disease).
Overdose. Depression is a risk factor for both parasuicide and completed suicide, and TCAs are commonly taken by those who deliberately self-harm. Dothiepin (dosulepin) and amitriptyline are particularly toxic in overdose, being responsible for up to 300 deaths per year in the UK despite the many alternative antidepressants that are available. Lofepramine is at least 15 times less likely to cause death from overdose; clomipramine and imipramine occupy intermediate positions.
Clinical features of overdose reflect the pharmacology of TCAs. Antimuscarinic effects result in warm, dry skin from vasodilatation and inhibition of sweating, blurred vision from paralysis of accommodation, pupillary dilatation and urinary retention.
Consciousness is commonly dulled and respiration depression and hypothermia may develop. Neurological signs include hyperreflexia, myoclonus and divergent strabismus. Extensor plantar responses may accompany lesser degrees of impaired consciousness and provide scope for diagnostic confusion, e.g. with structural brain damage. Convulsions occur in a proportion of patients. Hallucinations and delirium occur during recovery of consciousness, often accompanied by a characteristic plucking at bedclothes.
Sinus tachycardia (due to vagal blockade) is a common feature but abnormalities of cardiac conduction accompany moderate to severe intoxication and may proceed to dangerous tachy- or bradyarrhythmias. Hypotension may result from a combination of cardiac arrhythmia, reduced myocardial contractility and dilatation of venous capacitance vessels.
Supportive treatment suffices for the majority of cases. Activated charcoal by mouth is indicated to prevent further absorption from the alimentary tract and may be given to the conscious patient in the home prior to transfer to hospital. Convulsions are less likely if unnecessary stimuli are avoided but severe or frequent seizures often preceed cardiac arrhythmias and arrest, and their suppression with diazepam is important. The temptation to treat cardiac arrhythmias ought to be resisted if cardiac output and tissue perfusion are adequate. Correction of hypoxia with oxygen and acidosis by i.v. infusion of sodium bicarbonate are reasonable first measures and usually suffice.
Reboxetine is not structurally related to tricyclic agents and acts predominantly by noradrenergic reuptake inhibition. Antimuscarinic effects trouble only a minority of patients, postural hypotension may occur and impotence in males. It is relatively safe in overdose.
SSRIs have a range of unwanted effects including nausea, anorexia, dizziness, gastrointestinal disturbance, agitation, akathisia (motor restlessness) and anorgasmia (failure to experience an orgasm). They lack direct sedative effect, an advantage in patients who need to drive vehicles. SSRIs can disrupt the pattern of sleep with increased awakenings, transient reduction in the amount of REM and increased REM latency but eventually sleep improves due to elevation of mood. This class of antidepressant does not cause the problems of postural hypo tension, antimuscarinic or antihistaminergic effects seen with TCAs. Their use is not associated with weight gain and conversely they may induce weight loss through their anorectic effects. SSRIs are relatively safe in overdose.
The serotonin syndrome is a rare but dangerous complication of SSRIs and features restlessness, tremor, shivering and myoclonus possibly leading on to convulsions, coma and death. Risk is increased by co-administration with drugs that enhance serotonin transmission, especially MAOIs, the antimigraine drug sumatriptan and St. John's Wort.
Note. When SSRIs are compared with TCAs for patients who discontinue therapy (a surrogate endpoint for tolerability), most meta-analyses show a slight benefit in favour of SSRIs. Comparisons which exclude TCAs with the most prominent antimuscarinic effects (amitriptyline and imipramine) show either marginal benefits in favour of SSRIs or no difference between the groups. It is noteworthy that despite their pronounced adverse effects, amitriptyline and imipramine tend to be selected as 'standard' TCAs against which SSRIs are compared. Lofepramine, the second most prescribed TCA in the UK and the one TCA which causes little sedation, has few antimuscarinic effects and is as safe as SSRIs in overdose is; it under-represented in meta-analyses
Venlafaxine produces some unwanted effects that resemble those of SSRIs with a higher incidence of nausea. Sustained hypertension (due to blockade of noradrenaline reuptake) is a problem in a small percentage of patients at high dose and blood pressure should be monitored when > 200 mg/day is taken.
Nefazodone lacks antimuscarinic effects but may cause postural hypotension and abdominal discomfort. It appears to improve sleep quality and seems not to interfere with sexual function.
Mirtazapine also has benefits in rarely being associated with sexual dysfunction and in improving sleep independent of mood but like TCAs it may cause unwanted sedation and weight gain.
Trazodone has structural similarities with TCAs but probably acts by antagonism of postsynaptic serotonin receptors and presynaptic a-adrenoceptors. It is an option for depressed patients where heavy sedation is required. Trazodone also has the advantages of lacking antimuscarinic effects and being relatively safe in overdose. Males should be warned of the possibility of priapism (painful penile erections), attributable to the drug's blockade of -adrenoceptors.
Adverse effects include postural hypotension (especially in the elderly) and dizziness. Less common are headache, irritability, apathy, insomnia, fatigue, ataxia, gastrointestinal disturbances including dry mouth and constipation, sexual dysfunction (especially anorgasmia), blurred vision, difficult micturition, sweating, peripheral oedema, tremu-lousness, restlessness and hyperthermia. Appetite may increase inappropriately, causing weight gain.
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