Malhi & Farmer (Reference Malhi and Farmer1999) comment that in their clinical experience effective therapy for treatment-resistant depression necessitates enhancement of noradrenergic neurotransmission because of the effect this has on the typical symptoms of severe depression, which they speculate is more likely to lead to treatment resistance. It could seem from their letter that they advocate holding noradrenergic antidepressants in reserve for treatment-resistant depression. Such an interpretation would be unfortunate as it is probable that much of what is called treatment resistance results from the use of the wrong antidepressant. Roose et al (Reference Roose, Glassman and Attia1994) showed a substantial superiority for nortriptyline over fluoxetine in patients with melancholia. Melancholia is linked to abnormal response to the dexamethasone suppression test (DST) (Reference Carroll, Feinberg and GredenCarroll et al, 1981), and some studies have shown a preferential response to noradrenergic antidepressants in patients with an abnormal DST (Reference FraserFraser, 1983; Reference Kin, Nair and AminKin et al, 1997). The failure of many other studies to replicate that finding is likely to be due to a closer link between DST non-suppression and weight loss or sleep disturbance, than melancholia (Reference Mullen, Linsell and ParkerMullen et al, 1986). Nevertheless, no study has shown an advantage for a serotonergic antidepressant over a noradrenergic antidepressant in patients with melancholia, psychosis, or DST non-suppression.

In recent years, psychiatrists have been exhorted to avoid the dangers of the older (especially tricyclic) antidepressants in favour of the safer selective serotonin reuptake inhibitors (SSRIs). Their greater safety arises from an absence of cardiotoxicity, a lack of cognitive slowing, and minimal effect on blood pressure. Preferential prescription of an SSRI is justified on the basis that there is no evidence that any antidepressant is consistently any more effective than any other antidepressant in double-blind controlled trials.

Although it has not been conclusively demonstrated that noradrenergic drugs are better than serotonergic drugs for severe or melancholic major depression, there is a definite possibility that they are. More importantly, there is no evidence that they are worse than serotonergic drugs. Clinicians should preferentially prescribe a noradrenergic antidepressant for melancholic depression. Those who do so are likely to experience a decreased frequency of treatment-resistant depression among their patients, just as I have over the past 18 years.