Tolerability and ecacy are important factors determining the choice of an antidepressant. Older tricyclic antidepressants (TCAs) are associated with signiยฎcant behavioural toxicity, notably psychomotor and cognitive impairment and sedation. These eects are not seen with newer TCAs and selective serotonin reuptake inhibitors (SSRIs). Furthermore, TCAs are associated with a variety of somatic adverse events resulting from binding to muscarinic, a 1 -adrenergic and H 1 -histaminergic receptors, including dry mouth, visual disturbances and tremor. SSRIs are largely devoid of these eects, but gastrointestinal disturbances such as nausea and dyspepsia are common with these agents. Although the two classes of agent are broadly comparable in ecacy, there is some evidence that SSRIs may be less eective than TCAs in severely depressed patients. Hence, an antidepressant that is eective irrespective of the severity of depression and has a good tolerability proยฎle, should oer important therapeutic advantages. Clinical experience with milnacipran, a new serotonin and noradrenaline reuptake inhibitor, indicates that this agent meets these criteria.