The French philosopher Pierre Charron wrote that the true science and study of man is man. Professor Yatham and colleagues deserve commendation for their application of modern brain imaging techniques to study the mode of action of electroconvulsive therapy (ECT) in living patients with depression. ^{Reference Yatham, Liddle, Lam, Zis, Stoessl and Sossi1} The final assertion that their findings may put to rest the controversy about the role of brain serotonin in mediating the antidepressant effects of ECT may, however, be premature.

The authors suggested a common mode of action among ECT and antidepressant drugs, that is, the down-regulation of brain 5-HT₂ receptors. There is, however, evidence to question the overlap between the mode of action of ECT and antidepressant drugs that target serotonin. Selective serotonin reuptake inhibitors (SSRIs) inhibit the serotonin transporter. The gene that encodes the serotonin transporter has a promoter region that contains a polymorphism, and the allelic status of this polymorphism is associated with the probability of both improvement and recovery with an SSRI. The allelic status of this polymorphism is not associated with the outcome of ECT. ^{Reference Rasmussen and Black2} A proportion of patients with depression treated successfully with an SSRI will experience transient relapse during acute tryptophan depletion, which in turn depletes serotonin. This is not observed in patients with depression treated successfully with ECT. ^{Reference Cassidy, Murry, Weiner and Carroll3}

There is also evidence to suggest more of an overlap between the mode of action of ECT and antidepressant drugs that target catecholamines. A history of failure to recover with an SSRI during the index episode has no bearing on the probability of remission from unipolar non-psychotic major depression with subsequent ECT; in contradistinction, such a failure with bupropion, which does not target serotonin at all, or a heterocyclic antidepressant is associated with a reduced probability of remission with subsequent ECT. The only known allelic status that is associated with the outcome of ECT in patients with depression concern polymorphisms believed to affect the concentration of dopamine in the forebrain. ^{Reference Domschke, Zavorotnyy, Diemer, Nitsche, Hohoff and Baune4} Modern brain imaging techniques have also been applied to study the effects of ECT on brain dopamine: binding to the D₂ receptor in the rostral anterior cingulate, an area of the brain implicated in the pathophysiology of depressive illness, fell by 25% over a course of bilateral ECT, a finding compatible with an increase in the availability of dopamine. ^{Reference Saijo, Takano, Suhara, Arakawa, Okumura and Ichimiya5}

None of these observations on its own disproves the hypothesis suggested by the authors. Nevertheless, these observations too concern living patients with depression treated by ECT, and together cast doubt on the central role of brain serotonin in the mode of action of ECT in major depression.