Initial assessment
In a patient with symptoms suggestive of depression, the first step is to confirm the diagnosis of major depressive disorder and assess episode severity, suicide risk and functional impact. The predominant symptoms should be characterised, including fatigue, hypersomnia, insomnia, anxiety, agitation, chronic pain or sexual dysfunction, as well as symptom duration and the presence of previous episodes. It is essential to consider the overall clinical context, including age, medical comorbidities, polypharmacy and any history of response or intolerance to antidepressants.
Differential diagnosis
Before starting antidepressant treatment, medical or iatrogenic causes of depressive symptoms should be excluded, including hypothyroidism, vitamin B12 deficiency, anaemia, chronic inflammatory diseases or adverse effects of medicines. It is also important to distinguish major depression from adjustment disorders, bipolar disorder, substance use and primary anxiety disorders, as these conditions influence treatment selection.
Selection of antidepressant class
The choice of antidepressant should be individualised, bearing in mind that overall efficacy is similar across classes. Selective serotonin reuptake inhibitors are first-line treatment in most cases because of their favourable safety profile. The decision should be based primarily on the symptom profile, expected tolerability and risk of drug interactions rather than on rigid efficacy hierarchies.
SSRIs — clinical characteristics
SSRIs act predominantly on serotonin and have a favourable safety profile. Some have a more activating effect and may be useful in patients with fatigue and hypersomnia, whereas others are more sedating and may worsen somnolence. Sexual dysfunction and gastrointestinal effects are common class-related adverse effects. Differences in hepatic metabolism account for clinically relevant variations in the risk of drug interactions, which should be considered in patients receiving multiple medicines or specific treatments.
SNRIs — when to consider
Serotonin and noradrenaline reuptake inhibitors combine serotonergic effects with progressively greater noradrenergic activity as the dose increases. They are particularly useful in patients with low energy, anhedonia or chronic pain, especially neuropathic pain. However, they may be associated with increased blood pressure, tachycardia and a higher likelihood of discontinuation symptoms, requiring appropriate clinical monitoring.
Tricyclic antidepressants
Tricyclic antidepressants have robust efficacy but a less favourable safety profile. In addition to inhibiting serotonin and noradrenaline reuptake, they act on cholinergic, histaminergic and adrenergic receptors, accounting for the high frequency of sedation, weight gain, orthostatic hypotension and anticholinergic effects. The risk of arrhythmias and their narrow therapeutic index limit their use, particularly in older adults and patients with cardiovascular disease, and they are therefore reserved for selected situations.
Bupropion
Bupropion acts on noradrenaline and dopamine reuptake and has a more activating profile, with less impact on sexual function and weight. It is particularly useful in patients with marked anhedonia or sexual dysfunction induced by other antidepressants and may be used either as a replacement or as augmentation therapy. However, it should be avoided in patients at risk of seizures and used cautiously because of its potential for metabolic interactions.
Mirtazapine
Mirtazapine acts through modulation of presynaptic and histaminergic receptors, giving it a sedating and appetite-stimulating profile. It is particularly useful in patients with insomnia and weight loss but is less suitable when weight gain or somnolence are problematic. It has a low potential for interactions and a lower risk of sexual dysfunction.
Trazodone
Trazodone combines serotonergic antagonism with inhibition of serotonin reuptake. At low doses, it is frequently used for its sedative effect, particularly when insomnia is a predominant symptom. At higher doses, it exerts a true antidepressant effect. Attention should be paid to the risk of orthostatic hypotension and, rarely, arrhythmias or priapism.
Multimodal antidepressants
Multimodal antidepressants combine inhibition of serotonin reuptake with direct modulation of several serotonin receptors. In many patients, this profile is associated with better sexual tolerability and a neutral effect on weight, making them an option when adverse effects from SSRIs or SNRIs compromise treatment adherence.
Treatment duration and discontinuation
After a clinical response, antidepressant treatment should be continued for at least 6 to 12 months to reduce the risk of relapse. Discontinuation should always be gradual and planned, particularly with medicines associated with a higher risk of withdrawal symptoms. Periodic reassessment of benefit, tolerability and the need for ongoing treatment is essential for safe and effective management.
